JPS58103358A - Synthesization of antibiotic - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Chenamycin of formula I and several Streptomyces species (
The discovery of its analog 1-rubapenem antibiotic produced by strains of Streptomycea has given rise to strong interest in the synthesis of new carbapenems.

The chiral synthesis of chenamycin using L-asparagine rIIt- as a starting material was carried out using Zarraman (
Salzmann et al. and U.S. Patent No.
, 290,947, these are
It requires a long manufacturing process and harsh reaction conditions that cannot be used industrially. Related to this is the chemistry for introducing a side chain at the 4-position of azetidin-2-one.

If a carbon-carbon bond can be formed at the 4-position of azetidin-2-one, it will open up a wide range of possibilities for the synthesis of carbapenems. However, conventional methods have low yields, complex reaction conditions, and limited functional groups.

Accordingly, it is an object of the present invention to provide an improved process for the production of carbapenems, including chenamycins, henems, and oxapen-2-em-3-carboxylic acids. Furthermore, it is an object of the present invention to provide a simpler and more economical method of administering these antibiotics. Another objective is to provide new synthetic intermediates for these antibiotics. These and other objects of the invention will become apparent from the description below.

In accordance with the present invention, β-lactam formate is reacted with a strong base to convert it into a dianion, which is then acylated.
An acyl group is introduced at the 3-position and then converted to form the corresponding 3-(1'-aryl or 1'-alkyl, 1'-hydroxymethyl)-2-azetidinone-4-carboxylic acid. It is something. The same hydroxymethyl-2-
Acetidinone-4-carboxylic acid is obtained. The latter compound undergoes oxidative decarboxylation with lead tetraacetate to convert all carboxyl groups into acetoxy groups.

4-acetoxy compound f Lew with N-protection removed
Reaction with silyl enol ether in the presence of i s rlR and cyclization using rhodium acetate ([1) quantitatively yields a compound with a 1-carbapenem structure.Also, the acetoxy group is converted into triphenyl The penem is converted into a methylthio group and reacted by a known method to obtain a penem.

The present invention relates to chenamycin, penem, oxepane-2-
It is related to carbapenems including em-3-carboxylic acid. It particularly relates to new methods of synthesis of these antibiotics, including new intermediates thereof.

According to the present invention, asparaquine m of formula A is silylated to N,0°0-tristrimethylsilyl-asparaquinic acid of B by known methods. The known methods are
For example, use of hexamethyldisilazane under acidic catalysis, use of trimethylsilyl chloride in the presence of an amine, etc. Compound 2B is then reacted with a strong base to form formula C
7zetidinone formic acid is prepared. Strong base is PKa)2Q
Examples of suitable bases include compounds of the formula RMgX (R is an alkyl group and
trialkylaluminums such as; lithium dialkylamides such as lithium diisopropylamide; lithium methoxide, sodium isopropoxide, K-t
metal alkoxides such as -butoxide, magnesium-t-butoxide, and alkali metal hydrides such as potassium hydride. The compound of formula 0 is then N-protected to give compound gold of formula 2.

A B formula 2
The N-protected lactam formate is reacted with a strong base. This base converts the compound of formula 2 into the dianion of formula 3.

N-protecting groups are many nitrogen protecting groups that can be easily removed.
For example, it is a trisubstituted silyl group in which the substituent is an alkyl group or an aryl group. Suitable N-protecting agents are tributyldimethylsilyl chloride, diphenylmethylsilyl chloride, dimethylisobutylsilyl chloride. Examples of other N-protecting groups are tosyl or benzyl groups. Suitable strong bases are, for example, lithium diisopropylamide, lithium hexamethyldisilamide, lithium 2,2,6,6-titramethylpiperidide, butyllithium. Lithium diisopropylamide is a good base. The reaction may be carried out using, for example, tetrahydrofuran (TH
F) in an aprotic solvent such as diethyl ether or dimethoxyethane. The resulting dilithium salt of formula 3 is expressed as 0 1 formula R40X (wherein R4 is alkyl having 1 to 4 carbon atoms, fluorenyl having 2 to 4 carbon atoms, phenyl, 1 to 3 alkyl groups having 1 to 3 carbon atoms, halogen Atom 1~
3, 1 to 3 trifluoromethyl groups, phenyl substituted with amino, cyano or nitro. X is a leaving group such as halide, acetoxy, alkoxy, imidazole, pyridylthio, arylthio, alkylthio) for acylation by reacting with an acylating agent. The acylation is carried out in the presence of at least one excess of lithium diisopropylamide to produce a compound of formula 4.

3 Also, reacting the N-protected lactam M acid of formula 2 with at least 3 equivalents of base provides a means to perform the gold acylation without the addition of further base.

The dilithium salt of formula 3 can also be obtained by reacting the monolithium salt of 3a with one portion of lithium diisopropylamide. The monolithium salt of formula 3a is prepared by reacting t-1 equivalents of the N-protected lactamic acid of formula 2 with a lithium base such as lithium hydride, lithium hydroxide, n-butyllithium, lithium diisopropylamide.

A dianionic compound of formula 4 can be reacted with one equivalent of acid to form a monoanionic compound of formula 5, and can be reacted with two equivalents of acid to form a compound of formula 6.

The dilithium salt of formula 3 is subjected to an alkylation reaction with the aldehyde of 2R40HO to produce an epimer mixture of the hydroxymethyl dithiacid compound of formula 8a. This epimer mixture is
Oxidation with various reagents such as sodium dichromate-sulfuric acid-water, chromium trioxide, dimethyl sulfoxide-oxalyl chloride produces β-lactam keto acids of formula 6.

The keto acid compound of formula 6 is expressed as N a BH4, L i BI
I4.

The mixture is reduced by amine boron, H2/catalytic reduction, etc. to obtain an epimer mixture containing 28 R, s, 5-tt-substituted hydroxymethyl-β-lactam waxic acid compounds. However, when compounds of formulas 5 and 6 are reacted with 01Al1(0-0-OFa)2 (magnesium trifluoroacetic acid) and diisopropylamine boron, they stereospecifically produce compounds of formulas 7 and 8, respectively. I can make ink.

Further treatment of the compound of formula 7 with an acid yields compound 28.

l
88a The substituted hydroxymethyl formate compound of 28 or the compound from which its N-protecting group has been removed is reacted with lead tetraacetate to remove the substituted hydroxymethylacetoxyazetidinone of formula 9 in which R1 is H or its N-protecting group. A compound of formula 10 in which R1 is H is obtained. The compound of formula 9 in which R1 is H is then treated with known methods such as trifluoroacetic acid, tetrabutylammonium fluoride, methanol-hydrochloric acid, acetone-hydrochloric acid to remove the N-protecting group, and R1 A deprotected substituted hydroxymethylacetoxyazetidinone compound of formula 1O, where is 11, is obtained.

9.10 The epimer of the direct substituted hydroxymethyl formate compound of 28A is reacted with lead tetraacetate to produce the corresponding substituted hydroxymethylacetoxyazetidinone of formula 9A.

On the other hand, the compound of formula 8A can also react above 45°C (7
Even when R1 is H, formula 10
Compound A can be produced directly.

An epimer mixture of a compound of formula 9A or a compound of formula 10A from which the N-protecting group has been removed is oxidized in a conventional manner to give P
is a protecting group, for example t-butyldimethylsilyl
9 or a compound of formula 2o with P=H can be prepared.

A ketoacetate compound of formula 19 or 20 can be added to
BO2, Li BO2, amine boron or II2/
By catalytic reduction, R9It of formula 9.10, I
An epimer mixture containing the t-substituted hydroxymethyl-β-lactam kllt2 compound is obtained, but the compound of formula 19.20 is converted to Alt+(0-0-OFa)z
(magnesium trifluoroate M) and diisopropylamine boron to stereospecifically prepare the compound of formula 9.10.

The compound of formula 9 in which R, is other than H, the compound of formula 9 is (R1
H) k is prepared by reacting with a halide such as trimethylsilyl chloride, t-butyldimethylsilyl chloride, or 4-nitrophenylchloroformate.

Compound tl'' of formula 10, Rz and R3 are hydrogen, or each independently alkyl having 1 to 4 carbon atoms, fluorenyl having 2 to 4 carbon atoms, benzyl, phenethyl, silyl enol nitert of formula 11, halogenated Reacted in the presence of zinc or other Lewiar® such as boron trifluoride-ether solution, titanium tetrachloride, tin chloride, aluminum chloride, or in the presence of a highly reactive silylating agent such as trimethylsilyl triflate, Rs. is benzyl, allyl, alkyl or p-nitrobesidyl etc. Mono-substituted compounds of formula 11 where one of R2 and R3 is other than hydrogen are obtained according to Weller, J.
A, O, S, 96.1082 (1974), the benzyl acetoacetate is reacted with sodium hydride and, after reaction with n-butyllithium, the halide bearing the group to be introduced, for example methyl iodide, Manufactured by adding allyl bromide and benzyl bromide. A compound of formula 11 is obtained by diazotization and silyl enol ether formation. Disubstituted compounds of formula 11 in which R2 and R3 are both other than hydrogen are prepared in a similar manner.

2 The compound of formula 12 is then converted to the p-carbapenem by known methods, such as those set forth in Examples 15-18 of US Pat. No. 4,290,947.

Another method for preparing the compound of formula 12 is to prepare the compound of formula 9, lO't
- A compound of formula 13 in which Rz and R3 are the same as the compound of formula 11 and R is an alkyl group having 1 to 4 carbon atoms or a silyl group such as trimethylsilyl, and a Lewis compound, trimethylsilyl triflate, trimethylsilylation By reacting in the presence of a perfluorinated sulfonic acid resin, etc.,
It is characterized by producing a compound of formula 14.

The latter compound (formula 14) is saponified to remove Rt- when R is other than H (R1 is also removed when R is other than H). Activate the carboxy JL group with carbonyldiimidazole and then Mg(02CCH200zRs)
2 and finally introduce a diazo group to obtain a compound of formula 12.

Ra is Lr g Nat K9Mg 2 cu+Ag
an alkali metal or alkaline earth metal cation such as l Zn l cdt; a trialkylsilyl group such as trimethylsilyl, t-butyldimethylsilyl; a trialkylammonium salt such as triethylammonium, and R5 is a compound of formula 11 A compound of formula 10 is reacted with a 2-diazomalonate of formula 15, which is identical to the compound of formula 16, to form a compound of formula 16.

The compound of formula 16 was synthesized by rhodium ([1 catalyst-based fast ratio reaction V
This converts to a compound of formula 17. This further provides oxepane-2-em-3- of formula 18 via all compounds of formula V.
Converts to carboxylic acid. (In Formula 18, R7 is substituted or unsubstituted alkyl, ary JL, heteroaryl, heterocyclyl, or SR7 (R7f as shown above)). A compound of formula 17 is reacted with diphenylchlorophosphate in the presence of a tertiary amine (see Example 7, which represents a compound of formula V) and then a compound of formula V is reacted with diphenylchlorophosphate in the presence of a tertiary amine to form a compound of formula V, which is then reacted with alkyl, metal aryl, metal heteroaryl, metal heteroaryl, etc. Cyclyl, or n5Ry (metal is Li, Na, M
g, C'd; R7 is specified above) to form a compound of formula 18.

17 002R418C! O, the compound of formula 10 is reacted with sodium triphenylmethylthiolate to obtain the metal compound of formula 21. This compound (R, 1 other than H, e.g. t-butyldimethylsilyl) is converted into a compound of formula 22.23.24.25 according to the method described in British Patent 2.042,512. The compound of formula 22 is the compound of formula 21 f 0HOOO2Rs(R5
is the same as that shown in formula 11), and is reacted with 8002 and triphenylphosphine. The compound of formula 22 is AgN0. to prepare a compound of formula 23,
This is reacted with an acyl halide to produce a compound of formula 24. This compound is heated to obtain a compound of formula 25.

21 25 002RsAlso, 23
chlorothionate, and this compound was disclosed in European Patent Application No. 13.662 and British Patent No. 2,
The compound of formula 27a is heated according to the method of No. 048,261.

R1=tBuMe2Si, Rs=allyl J
” P N B 020 * Rs = P N
B The following examples illustrate the present invention and do not limit it. All temperatures are in Mr. Serra.

Example 1 The unprotected lactam azetidinone-4-carboxylic acid benzyl ester (20 mmol of 4,1,9°) prepared as described in U.S. Pat. No. 4,290,947 was dissolved in dry dimethylformamide (DMF) 15- Melt and cool to O''C.

This was added with t-butyldimethylsilyl chloride (3,16
5!7.21 mmol) followed by triethylamine (2.93 mA, 21 mmol). After stirring for 40 min at 0°C, the reaction mixture was dissolved in petroleum ether (low boiling point, 2
001! Add a pinch of water and wash with water. The organic layer was washed with water, 2NHα, H
Dry at step 4. The solvent was removed and N-t-butyldimethylsilylazetidinone-4-carboxylic acid benzyl ester was obtained as a free-flowing oil in 93 excellent yield (5,B56.9
).

B1 Preparation of deprotected lactam formic acid of formula 2 Protected lactam (4,452,!) dissolved in absolute ethanol (20m)
i', 14.1 mmol) in a solution of 10 predominant pd10 (
400~)'t-addition, 25°C at 40 psi hydrogen pressure
catalytic reduction for 30 minutes (until the theoretical amount of hydrogen has been absorbed). The catalyst was filtered off, the F solution was condensed, and the crystalline formula 2
of lactam gt obtained (mp, 143-145°, [
α: 1D-74°, C-1, cHcts).

Yield: 86 excellent (2,775 F).

C, dianion acylation and reduction Chiral (chi) of formula 2 dissolved in THF (2tnlV)
ral) acid (458 μm, 2 mmol) in THF.
A solution of 3.1 equivalents of lithium diisopropylamide (6.2 mmol) dissolved in (6 m) was added to O″C under nitrogen gas.
Add with a canyule. The solution is then stirred for 35 minutes.

During this time the temperature rises to 15°C. The solution was cooled to 0° C. and cannulated into a 0° C. cooled solution of acetylimidazole (3 mmol, 1.5 eq.) in dianion solution K, THF (4 m);
After stirring for 30 minutes, the temperature rises to room temperature. The resulting acetylated product was not isolated, but was incubated in an aqueous citric acid solution at 5°C.
After adjusting the pH to 7, the mixture f Na B H4 (
767%, 2 mmol) and stirred for 1 hour. After further adjusting the pH to 4 with citric acid, the mixture was partitioned between ether and water. When the ether layer is dried and distilled off, an oily substance is present (470Tn).
9.86 excellent).

In the NMR spectrum, formula 8A (R4=OH3)
It shows that the R, R, S and S, S, S isomers of are mixed in a ratio of 1.3:1.

D, Oxidative decarboxylation Hydroxyethyl formate of formula 8 (R4=OH3) (400 m 9.146 mmol) dissolved in DMF (10 ml) and glacial acetic acid (2 mA) was dissolved in lead tetraacetate (714 ~, 1
．． 61 mol) and heated at 35°C for 40 minutes to react. Cool to room temperature, remove DMF and acetic acid under vacuum and triturate the residue in ether (100 m). The ether layer was washed with an aqueous perchloric acid solution, saturated NaHO, and salt, and dried over MgSO, and the ether was distilled off to give hydroxyethylacetoxyazetidinone (formula 9).
R4=OH3) t' obtained in a yield of 841 (352 ■). This compound is reacted with trifluoroacetic acid to remove the protecting group to obtain a compound of formula 10 (R4=OHs).

If necessary, the Hoken group can be removed prior to reaction with lead tetraacetate.

E, hydroxyethylacetoxyazetidinone (R
4=C! A mixture of H3) (346~, 2 mmol) and the silyl enol ether (R = R3 = HI R5 = benzyl) (581, 2 mmol) of 2) was dissolved in dry dichloromethane (2 tnl) and dichloromethane (2
-) into a suspension of molten curved lead iodide (639rv, 2mm). After stirring at 25°C for 16 hours, it was poured into saturated NaHO03 water, and ethyl acetate (200rv) was added to the suspension.
mA). The ethyl acetate layer was washed with brine, and M
Dry over gSO4 and concentrate to obtain an oil. By silica gel chromatography, formula 12 (R2=Ra=H
+ R4=C) (3°R5=benzyl) compound at 89
Obtained at a yield of (,590m?).

F.
41'L)-3-[(R)-1-hydroxyethyl]-
4-[3-benzyloxycarbonyl-2-oxo-3-
diazopropyl]-azetidin-2-one (sorn9
．． 0.15 mmol), rhodium acetate (Ill, (0,
A nitrogen gas was introduced into the suspension of 1m9) for 10 minutes to remove oxygen. The mixture is heated to 78° C. for 1 hour, causing the starting solids to gradually dissolve. Next, it is cooled and passed through a v-pass to remove the catalyst. Concentrate solution F under vacuum, (5R, 68)
Benzyl 6-[(R)-1-hydroxyethyl]-
1-Azabicyclo[3,2°0]heptane-3,7-sion-2-carboxylate is obtained. 45■ (98 excellent)
Colorless oil.

G, Preparation of p-nitrobenzyloxycarbonylaminoethanethiol 600-diethyl ether (Et, 0)-75-H
, O was stirred in an ice bath, and 32I cysteamine m
Add m salt (mw=114; 28.1 mmol) f. 7,149 NaHα bathed in H20 of 75-
Add solution 3. At room temperature, excluding water bath, 270-
6,759 p-nitrobenzyl chloro-formate (mvi-216; 31.3
A solution of 1 mmol) is added dropwise over 1 hour. After 10 minutes, the layers were separated and the ether layer was soaked in 150-0,25 N
Hα and 200I111! Wash with saline solution. Each wash is extracted again with 100-Bt20 and the combined extracts are dried over anhydrous MgS04.

This is filtered and concentrated under a stream of N2. The crystalline residue is slurried with a small amount of ether and filtered. The pale yellow crystals are dried under high vacuum to obtain 4.7 g of p-nitrobenzyloxycarbonylaminoethanethiol (65% yield).

Il, (5R,68)benzyl3-(2-(p-nitrobenzyloxycarbonyl)-7minoethylthio)-6
-[(1'L) -1-hydroxyethyl)-1-7zabicyclo[3,2,0)-hept-2-7-one (5
R,68) Benzyl 6-[(R)-1-hydroxyethyl-1-azabicyclo[3°2.0]hebutane-
3,7-Sion-2-carboxylate (45m9.0
．． 147 mmol) in acetonitrile (3-) and cooled to 0°C. Diisopropylethylamine (22m
9.0.17 mmol) is added via syringe and stirred for 1 minute at 0°C. A solution of freshly recrystallized Bakashi's anhydrous p-) toluenesulfonic acid (51~, 0.156 mmol) in dry acetonitrile (1-) was then added and the mixture was heated to 0°C.
When stirred for 1 hour at (5R,68)benzyl 3-(p-
Toluenesulfonyloxy)-6-[(R)-1-hydroxyethyl]-1-7zabicyclo[3,2,0]-hept-2-en-7-one-2-carboxylate is obtained. This was cooled to -25°C, and 1-N-
Add a solution of p-nitrobenzyloxycarbonyl-aminoethanethiol (401n9.0, 15.6 mmol). The reaction mixture is left in the refrigerator for 16 hours. The mixture is diluted with 25-ethyl acetate, washed with brine, dried over magnesium chloride, and evaporated in vacuo to give a yellow oil. This was chromatographed on a silica gel plate (developed with ethyl acetate) and (5R,68)benzyl-3-[2-(p-nitro-benzyloxycarbonyl)amino-ethylthio]-6-[(R) -1 -Hydroxyethyl-1-azabicyclo[3,2,0]-
Hept-2-ene-7-thion-2-carboxylate is obtained as a yellow oil.

■ Production of chenamycin N-p-nitrobenzyloxycarbonyl chenamycin benzyl ester (9.5~, 0.017 mmol),
104 Pd/C-Bolhofer type is mixed in tetrahydrofuran (2-). To this, 0.1M dipotassium hydrogen phosphate solution (1,4d) and 2-propanol (
0.2 mj) and 40 p in Parr's apparatus.
Hydrogenate for 30 minutes at at. The mixture was filtered, the catalyst was washed with water (3×3 m), and the P solution was combined and extracted with ethyl acetate-ethyl ether. This is concentrated to ~3- and lyophilized. The resulting white powder is identical in all respects to natural chenamycin.

Example 2 Dianionic alkylation, oxidation, and stereospecific dry THF (
A chiral (0hiral) acid of formula 2 (6m) dissolved in
A solution of 90FQ, 3 mmol) was diluted with THF (2-
) into a solution of 2.07 equivalents of lithium diisopropylamide (6.2 mmol). 3 of the solution
Stir for 5 minutes, during which time the reaction temperature increases to 25°C. At this point, the dianion solution at 0° C. is reacted with excess acedoyldehyde (0.5 sd ) by stirring for 10 minutes. During this time the reaction temperature increases to 25°C. After cooling to 0° C. again, the mixture is made acidic with an aqueous citric acid solution and partitioned between ether and water. When the ether layer is dried and distilled off, formula 8 is obtained.
A hydroxyformic acid compound (R4=0H3) is obtained as an oil in a mixture with a hydroxyl epimer (7
34~. 904) B, epimer mixture of hydroxyformic acid compounds of oxidation 28A (R,
C1(,) (676 ml, 2.47 mmol) was dissolved in ether (15 ml), diluted with petroleum ether (5 ml) and cooled to -20°C.

To this solution, add 5 grams of 2 equivalent Na20r207 solution (10
0,! ii', Na20r207.300 ml, R2
A mixture of 0,136H2SO4 (total volume is made up to 500% with water) is added dropwise. After stirring for 1.5 hours at -20°C, partition between ether and ice water. The ether layer is dried and evaporated to obtain a 7-cetyl formate compound of formula 6 (Ra = CH3) as an oil.

(430m Section 9.64) A solution of the acetylformic acid compound (R4=CH3) (88m?, 0.32 mmol) dissolved in C0 stereospecific reducing ether (5-) is cooled to -78°C. First, magnesium trifluoroacetate (4251n9) then ether (1
-) isopropylamine boron (80 mg) 2
Add and stir for 1 hour. During this time the temperature rises to 25°C. The mixture is made acidic with 4 ml of citric acid solution, and the dichloromethane layer is dried and evaporated to give an oil with an excellent yield of 85%. N
In the MR spectrum, R, S, S isomers of 28 (R4=
CH3) only.

The R, S, S isomers of formula 8 were prepared in Example 1, Steps D-F.
The reaction is carried out according to the method described in 2009 to obtain chenamycin.

Example 3 Azetidinone formate-triethylamine A, N, 0.
Preparation of O-tristrimethylsilylaspartate L-aspartic acid (13,31,?, 100 mmol) is suspended in hexamethyldisilazane (607). This is reacted with concentrated H2S04 (4 drops) for 16 hours. Reflux (125°C).

Excess hexamethyldisilazane is distilled off under vacuum to obtain trisilylaspartate, N,0°0-tristrimethylsilylaspartate (32.9.S+, 94
), distilling the liquid product. b, p, 84-93°
C10,05 simple, B0 Preparation of azetidinone formic acid/triethylamine salt of formula C A solution of trisilyl aspartate (4,786 mmol) dissolved in ether (80 mA) was cooled to 0°C and diluted with ether (10 mA). ) dissolved in t-
Butylmagnesium chloride (2.3 M in ether)
% 9 ml g20.7 mmol) at 0 °C.
Add using cannula. The mixture is warmed to 25°C and stirred for 4 hours. Dowe for about 40d after cooling to 0℃ again
x50 resin (acidic) is added and the mixture is extracted with water. The aqueous layer is washed with Cα4 and checked by HPLO. yield··
・700m 9.44%. Water is removed by treatment with Et3N to obtain stable azetidinone formate-triethylamine salt 2.

Example 4 Synthesis of N-(t-butyldimethylsilyl)azetidinone formic acid of formula 2 A solution of azetidinone formic acid of formula C dissolved in MF (8 mj) in triethylamine acid is cooled to 0<0>C. This is reacted with triethylamine (5.6 mmol) and t-butyldimethylsilyl chloride (11, furimmol). After stirring for 1 hour at 0°C, the DMF'i was removed under vacuum and the residue was dissolved in ether. The ether layer is INHαlH
Washing with 20% brine, drying over MgSO4, filtration and concentration affords crystalline N-silyl acid of formula 2 (1.259
g, 98 regret), [α　-74° (C=1, OHα3),
m, p, 143-145°C.

Example 5 Preparation of an epimer mixture of deprotected hydroxyacetate of formula 10A and conversion to hydroxyacetate of formula 9.1o Preparation of an epimer mixture of A1 N-protected hydroxyacetate of formula 9A DMF (137 m/) and ice Epimeric mixture of hydroxyethyl formate of formula 8A (R4=CH3) (7,4'#) dissolved in acetic acid (27m).

A solution of lead tetraacetate (18,1711
41 mmol) and reacted at 32°C for 1.5 hours. After cooling to room temperature, DMF and acetic acid are removed under vacuum, the residue is triturated with ether (150 ml), insoluble lead salts are filtered off and solution F is washed with brine (125 ml).

Dry (Mg5O4) and concentrate to give an oil.

This was dissolved in petroleum ether, washed with brine, dried and concentrated to obtain an epimer mixture of formula 9 A (R4=CH3) nohydroxyacetate (5.51 g, 70
Yu).

80 Preparation of a deprotected epimeric mixture of hydroxyacetates of formula 10A, one equivalent of formula 9 A (R
The epimer mixture of hydroxyacetate of 4=CH5) is reacted with 1 equivalent of t-butylammonium fluoride solution and 2 equivalents of acetic acid in tetrahydrofuran (THF) in a bath of tetrahydrofuran (THF). Perform silica gel chromatography to obtain solid formula 10A
(R4=CHa), an epimer mixture of hydroxy acetate is obtained.

Direct Preparation of Hydroxyacetate of Formula 10A by Removal of Protecting Group from C0-protected Hydroxyacetate of Formula 8A Reaction of Step A was carried out at 170-75°C, with simultaneous de-silylation of the lactam nitrogen. , to obtain an epimeric mixture of hydroxyacetates of formula 10A.

00 of formula 19, enantiomerically pure, epimer of hydroxyethylacetoxyazetidinone of formula 9A dissolved in dichloromethane (11.7 g, 40.7 mmol, in CH2c1250), the solution was diluted with CH2α2 (1
Pyridinium chlorochromate (17,5-) in
5 g, 81.4 mmol) and anhydrous sodium acetate <1
．． 67 g, 20.35 mmol) at room temperature. After 12 hours, the mixture is diluted with 400 ml of ether and filtered through Floradil. The solvent was distilled off under vacuum and IO
,1,! Enantiomerically pure formula 1 of i'
9 ketoacetates are isolated (86 excellent).

E0 Preparation of defunded, enantiomerically pure ketoacetate of formula 20 Epimer of hydroxyethyl azetidinone of formula 10A (20 mmol) dissolved in dichloromethane (2'Od)
The solution was dissolved in CH2α2 (viridinium
Add to a suspension of rochromate (8.77 g 140 mmol) and anhydrous sodium acetate (0.84 mmol) at room temperature. After 8 hours, the mixture (520 (la/
Dilute with ether and filter through Floradil.

The solvent is removed under vacuum and the ketoacetate of formula 20 is isolated (yield: 74 lbs).

F0 Preparation of hydroxyacetate of formula 10 A solution of formula 1% (10.0 g, 35 mmol) in anhydrous ether (300 m) is cooled to -78°C. This was reacted with an ethereal solution of magnesium trifluoroacetate (2M solution, 86ml).

After stirring for 5 minutes, it is reacted with a solution of diisopropylamine boron (6.0 g) in ether (95 m).

After 10 minutes, the -78°C cooling bath is removed and replaced with a water bath.

The mixture was stirred for 40 minutes and added with cold IN Hα (200 ml
) is added. The mixture is extracted with ether (2×100 m/) and the combined organic layers are neutralized with aqueous NaHOOs. Wash with saline (200-) and dry (Mg5Oi)
Concentrate to give an oil (9.55.9).

The obtained oily hydroxyacetate i THF (40 m
l) and reacted with glacial acetic acid (3.5rnl),
Tetrabutylammonium fluoride ('l” If
React with IM solution in F, 33-). 1 at 0°C
After reacting for an hour, the mixture is concentrated to obtain an oily solid. Chromatography on silica gel yields 4°2I, formula 10
(69 excellent yield from starting material of formula 19), mp, 109-113°C [α]
D+86°, O=0.5, OHα3).

Example 6 Preparation of chain-extended hydroxyethyl A, benzyl 3-oxopentanoate of formula 12 Weiler, IL Am, Ohem++ Soc
* THF according to the method of 96.1082 (1974)
A suspension of sodium hydride (50% suspension, 2.1 g, 42 mmol) in (100 ml) was cooled to 0°C and benzyl acetoacetate, 7.68 g (40 mmol)
Add. After stirring for 10 minutes, n-butyllithium (2.5M in hexane, 16-) is added, the mixture is allowed to react for 10 minutes, and a bath of iodomethane (2,74 td, 44 mmol) in THF (4 fnl) is added dropwise. .

The mixture is allowed to react for 1 hour and slowly warmed to room temperature.

The reaction is stopped with INHα at 0° C. and extracted with ether. Wash with aqueous ether fN a HO03 and brine and dry with MgSO4.

The solvent was distilled off to obtain benzyl 3-oxopentanoate.

B. Preparation of benzyl 2-diazo-3-oxopentanoate According to the method described in US Pat. No. 4,284,575, benzyl 3-oxopentanoate (1,05,9,5 , 1 mmol), naphthalene-2-sulfonyl azide (1,306 g, 5.6
A mixture of triethylamine (0.76m, 5.4 mmol) is left overnight. (0°-25°C) After dilution with ether, H3P o4 aqueous solution, NaH
Wash with 003 aqueous solution, saline, and dry (MgSO<,)
do.

This was condensed and the oily residue was purified by silica gel chromatography (4:1, hexane:ethyl acetate).
82%) of benzyl 2-diazo-3-oxopentanoate.

NM几(Cα4)δ:1.2(311, t, J=7.
5112), 2.9 (2H, q, J=7.5Hz),
5.3 (2H,S), 7.3, (5H,S).

Preparation of the silyl enol ether of C, benzyl 2-diazo-3-oxopentanoate.Benzyl 2-diazo-3-oxopentanoate in THF (1,2-)
A solution of 3-oxopentanoate (330 m?, 1.42 mmol) (bexamethyldisilazane (0.37 ml), n-butyl lithium (2.5MsO, 71 m7 trimethyldisilazane) dissolved in i-THF (12 rnl) -78 of ethylenediamine (TMl et al DA-0,28td)
Add to the solution at °C. After 10 minutes, chlorotrimethylsilane (0.23 mA) is added and the mixture is slowly warmed to 25°0. After 1 hour the mixture is concentrated under vacuum and the residue is triturated with hexane. The hexane insoluble material is filtered out and the P solution is concentrated to obtain 394 mp (91%) oily silyl enol ether. NMI't(CDα3) δ: 1.6 (3
H, d, J=711z), 5.1 (2H, R),
5.1 (txt, q, J=7Hz), 7.2 (5
H,s).

D. Production of chain-extended hydroxyethylacetoxyazetidinone of formula 12 Hydroxyethylacetoxyazetidinone of formula 10 (1
12 Fv, 0.65 mmol), benzyl 2-diazo-3-oxopentanoate (394 m 9.1.3 mmol) was bathed in dry dichloromethane (2-) and dissolved in dichloromethane (2-). (under vacuum) into a suspension of zinc chloride (55 to 0.4 mmol). After 12 hours of gentle reflux, the mixture is poured into a saturated Na HC03 water bath (50 mA).

Extract with ethyl acetate (1oO-) and wash the ethyl acetate layer with brine, dry over MgSO4 and concentrate to give an oil.

A compound of formula 12 is obtained by convex mudgraphy on silica gel in a yield of 77%.

Example 7 5 of formula I dissolved in 2 T I-IF (250 ml)
-thiaso-4,6-thiketo-2,2-dimethyl-1,3
-Dioxane (diazo Meldrum acid) (170
,13,! p-Nitropencyl alcohol (153,14,!i+, 1.0 mol) is added to a solution of i+, 1 mol). The mixture was stirred at 25"C! for 8 hours. Diluted with ether (500mM) and filtered to remove the crystalline product.
Vacuum dried to give 223 g (84 widths) of the diazo acid of formula 15.
Obtain ester. R, is 11, and xts is p-nitrobenzyl.

5 Solution of diazo acid-ester of formula 15 (2,652 g, 10 mmol) in dichloromethane (10 m/) 1
Cool to 0° C., react with triethylamine (1,4 mA, 10 mmol) and add R,R,R-4-7 setoxy 3-(1-hydroxyethyl)-2-azetidinone of formula 10. After stirring the reaction mixture at 25°C for 4 hours, it was diluted with CH2αg (50 m) and brine (25 m
) and dried (Na2804). This was concentrated and the residual oil was chromatographed on silica gel to obtain the diazomalonate of formula 16 as a yellow solid (2.16y157). In the formula, R1 is H, R4 is methyl, and It5 is p-nitrobenzyl.

6 Diazomalonate of formula 16 (378~, 1 mmol) is suspended in dichloromethane (4-). This is reacted with a catalytic amount of rhodium (phantom acetate dimer (5~)). The slurry V is stirred at 40°C until it becomes homogeneous. The entire solution is cooled to 25°C. Hexane is added to this to completely precipitate the product. Filter and wash with hexane to obtain a compound of formula 17, where R1 is 11, R4 is methyl, and R5 is p.
- nitrobenzyl.

A solution of the oxapenem compound of formula 17 in dichloromethane was added to diisopropylethylamine (0,174 ml).
, 1.0 mmol) and diphenylchlorophosphate (268-, 0.99 mmol).

Use the resulting V solution as is without further modification.

A solution of compound ① was added to diisopropylethylamine (0,1
74 m/, 1.0 mmol) and N-protected cysteamine Vl (256 m, 1.0 mmol). The mixture is stirred at 25° C. for 14 hours to precipitate all the product. The crystalline diprotected oxapenem of formula 28 was isolated by filtration and OH2α
Wash with 2:hexane (1:1) to obtain 492g (0
．． 81 mmol, 834).

28002PNB CO□I( 8a Diprotected oxapenem of formula 28 (492771p.

0.81 mmol) to 104Pd10. THF (10,
0-), 0.1M dipotassium phosphate solution (70ml),
2- Mix with propatool (10 tnt). The mixture is exposed to indirect contact light for 40 minutes at 40 psj in a Parr apparatus. Filter the mixture and wash the catalyst with water (2x100y). All the p liquids were combined, vinegared rice was extracted with ethyl ethyl ether, and the aqueous layer was concentrated to 100%. Freeze-dry this to form a formula 18m.
Oxapenem is obtained as an entirely white solid.

Example 8 Preparation of a methyl compound of formula 14 from an N-protection-free compound of formula 10.
0-1-butyldimethylsilylazetidinone compound (1) where R1 is t-butyldimethylsilyl and R4 is methyl at
A solution of 4,41n (9.0.05 mol) is cooled in a dry acetone bath under N2 gas. Silyl enol ether of formula 13 where R and R3 are methyl and R2 is H (2
5 μt, 0.15 mmol) and Me3S 1OTf
(10 μt, 0.055 mmol) and the solution is slowly warmed to room temperature. Three hours later, on TLC,
Indicates the emitting substance. After 6 hours, the solution was diluted with 1EtOAe and
Wash with 54 NaHCO3, brine, dry with Mg5O, and filter. This is distilled off under vacuum to obtain a white solid (13.5rn9.86%).

In NMR, R1 is t-butyldimethylsilyl, R
Formula 14 where 4 is methyl, R2 is H, and R and R3 are methyl
This shows a 1=1 mixture of α- and β-methyl products. No starting material or N-silyl product signals are expressed.

Example 9 N-Protection of Formula 10, Preparation of Methyl Compound of Formula 14 from Compound Zn I2 (13,8Tn9.0.043 under N2 Gas)
mmol) completely melted. After cooling to room temperature, ZnI2
N-trimethylsilyl protection of formula 9, in which R1 is t-butyl-dimethylsilyl, 4 is methyl, and P-trimethylsilyl, dissolved in anhydrous CH2C7!2 (430 μt), was reacted with a solution of the compound, and then R,R , is methyl,
Silyl enol ether of formula 13 where R2 is H (40
μt, 0.25 mmol).

The resulting mixture is stirred vigorously for 2 hours at room temperature. It was then diluted with gtOAc, washed with 54 NaHCO3 and brine, dried over Mg5O, and evaporated under vacuum to give a clear oil (31.29).

The crude product is dissolved in anhydrous T HF (130 μt) and cooled in a water bath under N2 gas. Ac011 (9,8μ4
0.17 mmol), IM, Bu4 NF (80 μ
t) is added and the solution is left at 0° C. for 1 hour.

Dilute with EtOAc, wash with N20, brine, dry (MgSO4) and filter. This was distilled off under full vacuum, toluene was added, and distilled off again to obtain a colorless semi-solid (
24 m? ). The NMI'L spectrum shows the presence of a 5:4 mixture of α and β-methyl as in Example 8.

Example 10 Preparation of a methyl compound of formula 14 from a compound of formula 10 from which the N-protecting group has been removed ZnI2 (8
,0~,0.025 mmol, freshly melted under N2 gas)
suspend. This was combined with 7-cetoxyazetidinone (14°4-.0.05 mmol) of formula 10, where R is t-butyl-dimethylsilyl and R4 is methyl, and of formula 13, where R and R3 are methyl and R2 is 14. Silyl enol ether (
25 μt1-0.15 mmol). The mixture is stirred vigorously for 70 minutes at room temperature. Diluted with EtOAc and 5'I NaHC! 03. Wash each with brine and dry with MgSO4. This was filtered and evaporated under vacuum to give a clear oil (191 ny). NMR shows a mixture of N-trimethylsilylated starting material and N-trimethylsilyl α- and β-methylmethoxycarbonyl products in a ratio of 20:63:17.

The crude product was dissolved in anhydrous THF (75 μt), cooled in a water bath under N2 gas and dissolved in AcOH (5.7 μt).

0.1 mmol) and I M Bu4NF/THF (
Add 50μtVc and react for 1 hour. Solution 1BtOA
dilute with c and wash with N20.54 NaHCO2, brine and dry with MgSO4. This is filtered and evaporated under vacuum to give a white solid (11 m9').

NMR shows a mixture of 19 starting materials, 63 α-Me products, and 18 β-Me products. R1 is t-butyldimethylsilyl, R2+ R4
The ratio of the α and β products of formula 14, where R3 is methyl and R3 is hydrogen, is 3.5:1.

Example 11 Preparation of compound of formula 21 NaOMe (
A solution of 5, 4, 0.1 mmol) was cooled on ice and stirred.

To this, an azetidinone compound of formula 10 (17,51n9.0.1 mmol) in which R1 is H and R, is methyl and trityl mercaptan (27,6■, 0.1 mmol)
Add. Remove the water bath and stir under N2 gas for 1 hour.

Dilute with MeOH and evaporate under vacuum. Residue i EtOA
Wash with brine and dry with MgSO4.

If you take this off the coast and trade it under a smelly atmosphere, you will get an oily substance (52■)
. The crude product is subjected to chromatography using a 1×20×20 crn SGGF plate and developed with EtOAC. U
Remove the V absorption band, elute with E t OA C, rt
4-5O of formula 2I where l is I(, R4 is 0113
The O3 azetidinone is obtained as a foam (77 excellent) which slowly solidifies on standing.

Example 12 Preparation of compound of formula 26 1.83 g of formula 2 in dry at-izctz of 15-
To a stirred suspension of compound No. 3 (Rs=P-nitrobenzyl, R12P-nitrobenzyloxycarbonyl) at room temperature was added 347 Da of ethyl chlorodithioformate and 212
Add ~ pyridine. The mixture was heated under N2 gas at room temperature for 1
．． Stir for 5 hours. Insoluble matters were removed by filtration, and the p-liquid total Et
Wash thoroughly with OAe.

Partition with EtOAc/ice water/2.5 N Hα and separate the organic layer. Wash with saturated Naα, saturated NaHC03, dry with N2S04, and filter. leave,
Dry under nine air overnight to obtain a dark foam.

50 g of the product was added to a column filled with EM-60 silica gel and toluene: EtOAc.

Chromatography was performed eluting with 3:1, 1.5S
The product of formula 26 (R5=P-nitrobenzyl, RI=P-nitro-benzyloxycarbonyl) is obtained as a yellow foam.

Example 13 Preparation of compound of formula 26. Compound of formula 22 (R1 = t-butylmethylsilyl, R,
= P-nitrobenzyl) under stirring at room temperature.
．． 08-(2.04g, 1.48 eq, 2.58
x 10”-2 mol) of pyridine, then 0.15 MAgN03.139.4 m (
2,09×10-” moles, 1.2 eq.) is added. The mixture is stirred under N2 gas at room temperature for 0.5 h and concentrated to a dark solution. The concentrate is partitioned between 0142α2/ice water and
Separate the organic layer. Dry over N R2S 04, evaporate through E and dry under vacuum.

The above residue is dissolved in 125 m OH2α2 and stirred at room temperature. To this, 1,4-pyridine (1,38,!i'
, 1.74X10-2 moles, 1 eq), then 2
．． 25-ethyldithiochloroformate (2,929
, 2,09xl O-2 mol, 1.2 eq) total added.

The mixture was stirred at room temperature under N2 gas for 0.5 h, and insoluble materials were removed by filtration through Celite. Wash well with OH2 fake and distill off liquid E. Residue'jiEtOAc/ice water/concentrated H
Partition with α and separate the organic layer. Wash sequentially with saturated Nact, ice-cold dilute Na1 (00a aqueous solution), and saturated Naα.

After drying with anhydrous Na2SO4, the residue was distilled off and vacuum-dried overnight.

Using a column packed with CH2α2 with EM-60 silica gel of 1500~, elution was first performed with OH2α2,
Next, add 2 liters of OH2α2-EtOAc (20:
1) Finally, 9 liters of CH2α2:EtOA
Chromatography eluting with c (10:1) gives a yellow product in line 1/>8.97I, where RI and R5 correspond to the substituents of the starting material.

Claims (1)

[Claims] 1. The N-protected β-lactam formic acid of the formula is reacted with a strong base to convert it into a dianion, the dianion is acylated, an acetyl group is introduced at the 3-position, and the niacetyl group is reduced. to form 3-(1-hydroxyethyl)-2-7zetidinone-4-carboxylic acid; oxidative decarboxylation of this compound or an N-protecting group analog of the compound, converting the carboxyl group to a 7-cetoxy group. A method for producing an antibiotic intermediate, which is characterized by a process of nucleation. 2. The method according to claim 1, wherein the strong base is lithium diisopropylamide, lithium hexamethyldisilamide, lithium 2,2,6,6-titramethylpiperidide or butyllithium. 1 3. The acylating agent has the formula * CH3CX1 (X is a leaving group)
The method according to claim 1, which comprises: 4. The method of claim 3, wherein X is halide, acetoxy, alkoxy or imidazole. 5. The method of claim 1, wherein the reducing agent is NaBH4, LiBH4s amine borane, or catalytic reduction is used. 6. Claim 1 in which the reducing agent is magnesium trifluoroacetate and diisopropylamine borane
Section method. 7. The method according to claim 1, wherein the #i-forming decarboxylation reaction is carried out using 4 #: #I lead. 8. The method of claim 1, wherein the N-protected acetoxy compound is reacted with a silyl enol ether in the presence of a Lewis acid. 9, silyl enol ether is of the formula;
R5 is benzyl, allyl, alkyl having 1-4 carbon atoms, p
~nitrobenzyl). 10. Enantiomer of the following formula: 33a 5 8 8a 9A 10A16
17 (wherein, P is an easily removable nitrogen protecting group: R4 is alkyl having 1-4 carbon atoms, fluorenyl having 2-4 carbon atoms, phenyl, or
1-3 alkyl groups of 3, 1-3 halogen atoms,
1-3 trifluoromethyl groups, amino groups, cyano,
phenyl substituted with nitro; Phenyl or p-nitrobenzyl carbonate *R6 is benzyl, C1-4 alkyl, allyl, or p-nitrobenzyl; R7 is substituted or unsubstituted furkyl, aryl, heteroaryl, heterocyclyl, or Sks (Ry is as above); ph is phenyl; P
NB#ip-nitrobenzyl). 11. A compound according to claim 10, which has one of the following enantiomers: (P in the formula is as defined in claim 10). 12, Equation 16.17 in claim 10.
An intermediate for producing an oxapen-2-em-3-carboxyl version compound consisting of compound No. 18 or (1). 13. Process for preparing a compound of the formula: (wherein R1 is hydrogen and It is as defined in claim 10) by reacting the compound of the formula with sodium triphenylmethylthiolate. . 14. A process for producing a compound of the formula: % formula %, characterized by reacting the compound of the formula: with chlorothionate (wherein R1 and R5 are defined in claim 1
(as defined in item 0). 15. A process for producing a compound of the formula: wherein the compound of the formula: is reacted with a compound of the formula: 2 (R1+R4*Rs is as defined in claim 10, R6 is Li, (Na, Mg, Cu, Ag, Zn, Cd). 16. A method for producing a compound of the formula: by decomposing the compound of the formula with a rhodium head catalyst (wherein R1+R4tR5 are defined in claim 10). 17, a compound of the formula: metal alkyl, metal aryl, metal heteroaryl, metal heterocyclyl, or H8R4 (Rr is substituted or unsubstituted alkyl, aryl, heteroaryl, heterocyclyl, or SRw, the metal is Li, Na,
. K . 18. A process for producing a compound of the formula: characterized by reacting the compound of the formula: with a compound of the formula: 3 in the presence of a Lewis acid, trimethylsilyl triflate or trimethylsilylated perfluorosulfonic acid (wherein R4 is As defined in claim 10, R is alkyl having 1-4 carbon atoms, R2 and R3 are H1 alkyl having 1-4 carbon atoms, alkenyl having 2-4 carbon atoms, benzyl, phenethyl.) . 19, a compound of the formula: is reacted with a strong base and hydrolyzed to form (S)-
7. A method for producing a compound of the formula: characterized in that it is made of gold cetidine-2-one-4-formate.