JPS5951291A - Oxadethiacephalosporin intermediate and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is H or OCH3; R2 is lower alkyl; R3 is CH3, halomethyl, or -CH2S-Het (Het is heterocyclic group which may have substitutent group); A is H or COOH-protecting group]. EXAMPLE:7beta-Amino -7alpha- methoxy-2alpha-methyl -3-(1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cephem-4-carboxylic acid. USE:A synthetic intermediate of 7beta-acyl-2-alkyl-1-oxa-1-dethia-cephalosporin compound which is a strong antibacterial agent. PROCESS:The compound of formula I can be prepared by (1) cyclizing the novel azetidinone compound of formula II (RCO- is acyl; ph is phenyl; A' is COOH- protecting group), (2) eliminating the RCO-group from the resultant compound of formula III, (3) reacting the product with an aromatic aldehyde to obtain the compound of formula IV (R4 is aromatic group), and (4) carrying out the steric inversion of the 7alpha-NH2.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 1-oxa-1-dethiacephalosphorin compound having a 2-alkyl group and a method for producing the same.

To explain in more detail, the 5-pronged product loses its antibacterial power.
-Alkyl-1-oxa-I-dethiacephalus?
The following general formula (1) is useful as an intermediate used to synthesize the phosphorus 9 i9 form [in the formula, R111i is a hydrogen atom or a methoxy group, R2 is a lower alkyl group, and R3 is a methyl group]. Biting style-CH2-8-■■ot (Ijj, L, H
e t is 1;' (conversion.

(represents a heterocyclic group which may have a group);
Furthermore, the first gist is a 7β-amino-2-alkyl-1-oxa-1-dethiacephalosporin compound represented by the following formula: A represents two water atoms or a carboxyl-bearing N'i group.

Recently, bl-oxer 1-dethia 3-cephem compound 4V
Synthetic research on oxacephalosporin (oxacephalosporin) is progressing (e.g., Special Publication No. 53-25551).
; 114(). Inventor r)? :l: I'm currently researching the new synthesis of Ogisacephalus moromirin, Oxacephalus r+? / We found that compounds with an alkyl group at the 2nd position of the nucleus have enhanced antibacterial activity and increased resistance to β-lactamase compared to compounds without an alkyl group. (See City Application No. 57-127574 Mei? 111 filed by 11 people). After intensive study and research on the synthesis method, the present invention was completed as a result of the research.

7β-amino-2-alkyl-1 of formula (■) of the present invention,
-Ogisa 1-Dethiasenoalos, I? The phosphorus compound is a new compound that has not been described in any literature.

Specific examples of the compounds of the present invention are as follows.

(1) 7β-amino-7α-methoxy-2α-methyl-
3-(+-methyl-1)I-tetrazol-5-yl)
Thiomethyl-1-oxa-I-dethia-3-cephemu-4-carboxylic acid or its diphenylmethylgostyl (217β-amino-2α-methyl-3-(1-methyl-I H-tetrazol-5-yl)thiomethyl-1 −
Oh! -Deboer 3-cephem-4-carboxylic acid or its diphenylmethyl ester l II-tetrazol-5-yl)thiomethyl-1-oxa-1-deboer 3-cephenol-4-carboxylic acid or its diphenylmethyl ester (4) 7β -amino-7α-methoxy-2β-methyl-3-(+-methyl-111-7・trazol-5-yl)thiomethyl-1-oxa-1-dethia 3-cephem-4-carboxylic acid) J: Sono J
7-c = lumedyl ester (5) 7β-amino-2β, 3-dimethyl-1-oxa-1-detear 3-cephemu-4-carboxylic acid or its diphenylmethyl ester (6I 7β-amino-2α, 3-dimethyl-1 -Okitsu 1-Dechia 3-Sephemu 4-Carbon Kenkimata H
The diphenylmethylnisdel compound of general formula (I) of the present invention can be produced by a method whose basic step is to cyclize an azetidinone derivative obtained by condensing an oxazoline derivative with an α-hydroxyalkanoic acid alkyl ester. This is done by 4fJ. The manufacturing method using the following formula (the aim of starting from an azetidinone derivative represented by lull) is shown in the process diagram! The diagram is shown below.

---, -field engineering e
Therefore, according to the second gist of the present invention, the following general formula [wherein the group RCO- represents an acyl group, R2 represents a lower alkyl group, and R3 represents a methyl group, a halomethyl group or a group of the formula -
CH2-S -Hat (Het is a heterocyclic group which may have a substituent), p+1 is a phenyl group, and A' is a caryl+'xyl group. The azetidinone compound of the following formula (where RCO
-+ R2* R31A' has the same meaning as above) (produces a t-cephem compound, and
-The amino group is removed by a known reaction to produce a compound of the following formula (wherein R2tR31A' has the same meaning as above), and this compound is reacted with an aromatic aldehyde to form the following compound. A Schiff base-type compound of the formula (wherein R21R3.A' has the same meaning as above and R4 represents an aromatic group) is produced, and the Schiff-based 7α-amino group of this compound is converted to , a known configuration inversion reaction, or a known configuration inversion reaction involving 7-position, 9-methoxylation.
・Produce a compound (R3, R4, A' has the above meaning pi;), further cleave the compound or C-, the group R4-CM= of the ship base by a conventional method, and if necessary for C]. 4'
! 7β-amino-2-alkyl-1-oxa-1 represented by the general formula (wherein R1, R2+ 13 have the above-mentioned meanings, and A represents a hydrogen atom or a carboxyl retaining group), −
Dethiacephalus, J? A method for producing a phosphorus compound is provided.

In the compounds of general formulas (1) to (■) in method 1 of the present invention, IL R++ R21R3 and A' all have the above-mentioned meanings, and R4 is an aromatic group, such as t;
An aryl group that may be substituted with 4-hydroxyphenyl and a phenyl group are shown below.

R+ in the starting material (■) and intermediate substances (■) to (■) used in the compound (I) of the present invention and its production method
R11R21R3t A' will be explained in detail below. In the acyl group '2' of the group RCO-, in general, any aromatic acyl group can be used. Therefore, the group R can be an aromatic group, such as an aryl group, a phenyl group or a phenyl group on the 11 side. Group 9 arylargyl group,
It can be an aryloxyalkyl group, an aralkyloxynochloride or a triphenylalkyl group. For example, the group R
CO- is preferably a phenylcarbonyl A-, phenylacetyl, benzyloxycarbonyl, phenoxymethylcarbonyl or tritylcarbonyl group.

The lower alkyl group as R2 means an alkyl group having 1 to 4 carbon atoms, and both α and β configurations exist, and α
, β coordinations are preferably methyl groups.

Examples of the heromethyl group for R3 and I- include monosubstituted methyl groups of chlorine and bromine. That's sweet, R3 is a group -CI
I2-S-)1ot is useful, but here)(e
The yakuryoku group represented by t is a 5-membered heterocyclic Z (including 1-,
Preferable examples include C'detrazolyl group and triazolyl group.

A thiadiazolyl group is present. Examples of the substituent on this double-hydrocyclic group include a lower alkyl group having 1 to 4 carbon atoms, particularly a methyl group or a carboxy lower alkyl group, which is conventionally used as a substituent at the 3-position of known cephalosporins What is shown is also possible.

Schiff base residue R4-CH= VC or group R4 is generally an aromatic group, especially aryl; 11, preferably 4-hydroquinphenyl. As a substituent, a lower alkyl group such as methyl, inglovir/t-butyl, etc. may be present, and substitution at the mano position $H, 1rj-3, 5-!:/fi is preferred. .

The group A' can be a hydrogen atom or a carboxyl-protecting group, and as a carboxy-protecting group, it is conventionally used as a cephalic group. Phosphorus, all those commonly used for penicillins can be used, such as substituted or unsubstituted aralkyl groups such as &-, +, A' c-t diphenylmethyl, benzyl, -nitropenzyl groups, and jt- butyl,
It can be an alkyl group such as trichloroethyl or an unsubstituted alkyl group.

The method for producing the compound of general formula (1) according to the present invention will be explained in more detail with reference to process diagrams.

First, the cyclization reaction from the compound 'Mt
・=ittig) It is a reaction in which 1-cyclization is added to the reaction. The reaction temperature is in the range of 40 to +20'C, preferably 1
It is in the range of 00 to l 200C noi'ij. As the inert solvent, ethers such as THF, dioxane, benzene, toluene, xylene, and nomethoxyethane are used. In order to prevent side reactions, this reaction is preferably carried out in a nitrogen or argon stream, and a catalytic amount of --hydroquinone may be added as an antioxidant.

The α and β coordinations of R2 in compound (Ill) will be α-coordination when R2 in compound (TI) is R-coordination, and will be β-coordination when R2 is S-coordination. The two steps of producing compound (1) from compound (Ill) and further producing a thick base type compound of compound ('V) can be carried out by conventional methods. That is, the former (In
)→Qv) step is the so-called iminohalide, iminoether method (see Japanese Patent Publication No. 41-3862), and the latter step (IV)→(V) is carried out to react with L aromatic aldehyde. Basic and %b
; The method of retei disclosed in Publication No. 1, 1973-50394,
For example, it can be carried out by dehydrating and condensing an aromatic aldehyde such as 3,5-di-t-butyl-4-benzaldehyde in an inert solvent such as benzene, methylene chloride, or ethyl acetate, thereby forming compound (v). Gai4? It will be done.

The inversion reaction that produces compound (VT) from compound (v) involves dissolving compound (V) in an inert solvent, first adding an oxidizing agent, converting it into sigma, and then simply adding a reducing agent after removing the oxidizing agent. At this time, a steric inversion reaction of the side vessel at the 7-position occurs, and compound (Vl) is converted to 8. The solvent used in this reaction is one commonly used in the reaction of β-lactam compounds, with chloroform, methylene chloride, etc. being preferred. As the monotonizing agent, manganese I nickel peroxide, quaternary 1'k lead, and dichlorodicyanobenzoquinone (DDQ) are preferably used.

37 base agents include NaBH3CN (sodium cyanoborohydride), NaBH4 (sodium borohydride), Et4NBH4 (tetraethylammonium borohydride), or Li (t-BuO)3L/
11 (tertiary butyl-oxyaluminum hydride, lithium) is preferably used. ) to produce a compound (\■) if
This can be carried out by an inversion reaction involving methoxylation at the 7-position, and the method disclosed in JP-A-50-50394 can be applied to this.

In this way, r', j Radada compound (VI) and (
(2) is then subjected to a Schiff-Hanawa group)/]γ (cleavage) reaction to lead to the desired intermediate compound (1).

The decomposition (cut!n'i) of this ship base is carried out using a known method.
For example, actual hrQ can be achieved by the hydrolysis method disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 50-50394. Furthermore, if desired, the carboxyl-binding group (A'
) can be removed using conventional methods.

The object compound (1) of the present invention is a 7β-acyl-2-alkyl-1-oxa-1 which has strong antibacterial activity by appropriately acylating the amine group at the 7-position and then removing the carboxyl-retaining SM. -Detearcephalos yf, which can be induced into IJ compounds and is useful as an intermediate.

As a specific example of producing a compound having an antibacterial effect from the compound (1) of the present invention, the above-mentioned Japanese Patent Application No. 57-127
This is clearly stated in Specification No. 574.

Compound (Jll-
The compound of the general formula (II) is, for example, a compound of the following formula ( ■) ph (However, Me is a methyl group, A has the above meaning, p
3-benzhydrylmethyl-2-C (l R.

5S)-3-phenyl-7-oxo-4-o-1tzar2.6-tazabicycloc3.2. o〕hen0]-2-
en-6'il] Boudot 2-en-eight is Journa
l of Chemical 5ociety+ P@
rkin I, 1932 pages (1'?75)
It can be synthesized in multiple stages starting from ゛, 4 times.

D of the following formula (wherein R2 is an alkyl group having the same meaning as R2 in general formula (I), and B is an alkyl group such as an ethyl group) for the compound Oj:+)
When L-α-hydroxyalkanoic acid alkyl ester is reacted in the presence of trifluoromethanesulfonic acid in a chamber width, the following formula () (ph, R2, B have the same meanings as above, hereinafter F) (3R ,'4R)-4-((11ya)-1-alkoxycarbonylalkoxy)-3-benzamide-1
-(1-conservative carbonyl-2-methylprop-1-enyl)-azetidinon-2-one.

Following formula % formula % xicalginylalkoxy)-3-benzamide"'
I'-(+'-protected carbonyl-2-methylglow-1-enyl)-azetidinon-2-one is obtained as a diastereomeric mixture. When this was subjected to silica gel chromatography developed with benzene-ethyl acetate (7:l), the compound of formula (Vl) and the compound of formula (■) were separated from each other in the form of The general formula for (
■) In place of the compound 11, shi, no, the corresponding D
The (R form), 5 form (8 form) compound ([) is added to the compound 11 of the general formula (tm) + jzc horn F
, J'.

The halides of the general formulas (X) and (M) having the desired stereochemistry can be obtained without chromatography (Reference Example 6).

Furthermore, in order to convert the desired cephem ring from the compound (X), (M) as the subsequent process ('l:?:), the general formula (X
), (XI) Compound Zunawaji azetidinone compound 1
Perform step 4-5 of pre-treating the side chain at position and position 4. The process will be explained starting from the step of treating 611 at position 1 of the azetidinone compound (see Reference Example 1). Taking the compound of formula (M), When J is oxidized by reacting with ozone gas in scorched methylene at 1 degree below 0°C, an acclimatized product (unstable) of the following formula % is formed (same (k This reaction is related to the applicant's application filed in 1984, 1984.
No. 911). Cut moss 1 with vinegar at low temperature! When reduced with IEm powder, alcohol r,t::6s of the following formula is formed. Formula (XIII)
Chlorination of the alcohol with thionyl chloride in the presence of pyridine in methylene chloride produces the nochloride conductor. The chloro compound of this formula (X+~γ) was prepared as a trialkylamine in chloroform.
When treated with triphenylphosphine in the presence of a tertiary amine at room temperature, a reaction occurs in which the chlor group replaces the IJ phenylphosphoranylidene group (phosphoranylidene formation step). This produces a compound of the following formula.

Since the pretreatment step for the 1st-position side is completed here, we move on to the pretreatment step for the 4th-position side of the azetidinone compound. When the alkyl group (B) is eliminated by hydrolysis under alkaline conditions, the corresponding carboxylic acid compound (corresponding to the one in which -OB in formula (XV) becomes 10H) is obtained. This catalytic acid compound activates the group -COOB before being subjected to the next reaction.This activation includes, for example, active esterification. For this purpose, when the carboxylic acid compound is treated with chloroformic acid ethyl ester of the following formula % (%), ethoxycarbonylation occurs, thereby obtaining a compound of the following formula.

A compound of formula (XW[) is treated with diazomethane in ethyl ether at low temperature to obtain a noisomeric diazo compound. When this diazo compound (XWII) is reacted with hydrogen chloride in dioxane, the diazo group becomes a chloro group and f”
i q%sa:],ru. This gives the following nochlor compound 11). To this chloro compound (II'), a heterocyclic thiol compound of the following formula % (where Hot does not represent a heterocyclic group) is added in methylene chloride in the presence of pyridine to obtain a compound.

In the above explanation, the case where starting from the compound of the general formula (X A similar treatment is repeated for the compound Vc and C, and after each treatment, a cyclization reaction is carried out to form a cephem ring.

In the former case, the 2nd position of the cephem ring is α-coordinated, and in the latter case, the 2nd position of 1 cephem 3A1 is υ, β self-position.

Furthermore, the 1st position ft1 of the compound of formula (X) and 01[)
In the processing of the ij button and the 4th place, the L1 koji may be added first.In either case, each reaction is carried out under the same reaction conditions as described above. Reference example 4 is an example in which the 4-position analogous chain is treated first.

Among the compounds of the present invention represented by general formula (1), R
3 or halomethyl group 1; for example, it can be synthesized by reacting the compound of general formula (■) with the above-mentioned cyclization multiplex, or R3 of the synthesized general formula (Ill) is a halomethyl group. It is preferable to convert the compound of the general formula (H') into a compound of the general formula (H) and cyclize it to form S.When R3 is a methyl group, the starting material, that is, the compound of the general formula ([ The method for producing a compound in which R3 is a methyl group in compound 1) is shown in Reference Example 5 (method in which the 4-position of azetidinone is converted first). Halomethyl group (
It can be obtained by reducing the compound Shibi of No. 2. The most suitable halide site for the halomethyl group during reduction is iodine.◎ This halomethyl group is reduced to the 1st position of azetidinone.

The conversion reaction can be carried out in the same way regardless of which of the 4th positions is used first. Below, examples of the method of the present invention and the method of preparing the raw material compound will be explained with reference to examples of the present invention. will be specifically explained in detail; however, the present invention is not limited to these examples.

Example 1 (1) 7α-benzamide-2α-methyl-3-(1-
Methyl-1)! -tetrazol-5-yl) thiomethyl-1-oxa-I-butyal 3-setuemu 4-carboxylic acid diphenylmethylentel σ) produced by the following formula % formula % (where ph l:] represents a phenyl group, and Δ□Te represents a methyl group. , also -Tz-Me represents a 1-methyl-tetrazol-5-yl group), that is, (3B,4R)-4-((IR)-3-(+-methyl-I H- Tetrazol-5-yl)thio-2-oxo-1-methylzolo-1?xy)-3-pendzamide-1
-(+-diphenylmethoxycar-?niru1-1-!
J phenylphosphoranylidenemethyl)azetidine-2-
On's 2・o o g wo+-luene 75mA I/L
After dissolving L and adding 50 mg of Irquinone and heating under reflux for 9 hours, a cyclization reaction occurs. The reaction solution was condensed and purified by column chromatography on silica gel (developing medium benzene-vinegar Q'':ethyl (3:l)).

The following formula 1.+7 of the title compound! / Get (section 86).

IR (CJIC13), v (ttn-'):
1787.171L 1672°ax 1600, ΔR (CDC13), δ: 1.5
1 (3H, d, J = pm 6-9 Hz, 2 CH3), 3.81 (31
1,1+, Tetrazole I -CH3), 4.1
7.4.40 (2H, ABq, J = 1311i
, -CI■2S-), 4.130 (IH,
q, J = 6.9 Tlz, 21[), 4-
81 (IH, dd, J = 7.5.I-OHz,
7-fl), 5.28 (+1(, d, J= 1.
0)IZ, 6-II), 6.94(IH,s
, -CIIph2), 7.10-8.70 (15
H, m.

C6H51X3).

(2+ 7(Y-amino-2α-methyl-3-(1-
Methyl-I II-u-trazol-5-yl)thimemethyl-1-oxa-1-dethia-3-cephem-4-carvone l'i:2 Formation of diphenylmethyl enotel PCl5 840 t g <(methychloride t/ 24
0.48 nt of pyridine at 2.0°C in r8 solution in ml.
Add and stir for 30 minutes at the same temperature 〇This reaction? l'/C 120011 of the product of the previous item (1)
Add 2 ml of methylene chloride I containing 9 dropwise at 1
．． , 30 minutes at the same temperature, O ~ 25 cC Tel: t '14''t Ro N Hi O0C to cold 1; D L
, add 30me of methanol and incubate for 10 minutes at the same temperature.
1: 7) at 25'C for 40 minutes.

An elimination reaction of the benzoyl group (phco-) occurs.

Pour the reaction mixture into 60 mg of ice water, stir for 30 minutes, and condense the O residue. Dissolve in 0 ml of O'+:la minichill, wash with saturated sodium bicarbonate water and water, dry over MgSO4, and condense.

The remaining proboscis was subjected to silica gel column chromatography (M
Purification with rM sol. M='benzene-ethyl acetate (1:l) yields 630+v (65%) of the title compound of formula %.

IR(CHC/3), νmaX(on-'):
1779.1713.1620 (317α-(3,5-
di-t-butyl-4-hydroxypenzolidenamino)
-2α-Methyl-3-(1-methyl-I H-tetrazol-5-yl)thiomethyl-1-oxa-1-dethia 3-cephem=4-carboxylic acid Before the formation of sophenyl methyl ester J (formation of 21 6009.3.5-di-t-butyl-4-hydroxypendualdehyde 312cm was dissolved in Hensefu 60 dK*Dean-5tark
After heating under reflux for 45 minutes in a device of

ph is a phenyl group + -Tz-Me is an I-methyl-I H-tetrazol-5-yl group).

(4) 7β-(3,5-di-t-butyl-4-hydroxybenzylideneamino)-7α-methoxy-2α-methyl-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-1- Oxa-1-dethia 3-cepheno, -4-carboxylic acid diphenylmethyl ester Production 910q of the product of the previous section (3) was dissolved in 15me of methylene chloride.
Dissolved in MgSO4660 under ice-cooling, and added chive peroxide'I
600 ryy is added and stirred at the same temperature for 10 minutes, it is oxidized to a benzoquinone type intermediate having no stereochemistry. The reaction solution was filtered, and the filtered material was poured into 15 m of methylene chloride.
Wash with e and mix P solution.

To this P solution, add 30% of methanol under water cooling, and add 30% of methanol at the same humidity.
When stirred for 0 minutes, an inversion reaction occurs simultaneously with the introduction of the 7α-methoxy group. When the reaction solution is concentrated, 9.00 ~ of the title compound shown by the following formula is obtained.

(5) 7β-amino-7α-methoxy-2α-methyl-
3-(l-Methyl-IH-tetrazol-5-yl)thiomethyl-1-Oyaza 1-dethia 3-/7Femu 4-Carbon Agency 2 Production of diphegol methyl ester 900 capes of the product of the previous item (4) of ethyl acetate 151ff
/ and added methanol I 5 + nll containing 400 rny of Girard T reagent and stirred at room temperature for 2 hours to remove the substituted penzolidene group from the 7/9-amino group.
'A quasi-reaction occurs.

Concentrate the reaction solution and add 6! of vinegar to the residue. ? Dissolve in 20% ethyl, wash with water, and dry to 60% with 4g SO4.

The residue was filtered into a column of silica shell ``1 Madographie'' (
When the compound was prepared with a developing solvent of Pe/Zene-vinegar (2:1), 40 s my (64 width) of the title compound, represented by the following formula, was obtained.

IR(, CI(C13), νmaX(Cm-'):
1782. 1720.1603NMR (DO13
), δ: 1.55 (311, d, J =
6-13 Hz.

29m 2-CH3), 2. IQ (2H, br, s, amino), 3.52" (3H1fi, -0CH3),
3.79 (31(, 8, Tetrazole I-CH3),
4. +5. 4.48 (211, ABq, J
= 14I(z.

-CT (2S -), 4.85 (IH, q, J
= 6JHz, 2H).

4.97(IT(,Il, 6H), 6.90(
II(,s, -CHph2).

7.15-7.70 (Ion, m, C6H5X2) Example (1) 7β-(3,5-di-t-butyl-4-hydroxybenzylideneamino)-2α-methyl-3-(1-methyl- I H-tetrazol-5-yl)thiomethyl-
Production of 1-oxa-1-dethia 3-cephemu-4-caldenoic acid diphenylmethyl ester 16 Example 11 650 μ of the product at the top (2) was mixed with 10 I+Xf of methylene chloride! G'+ x* with I, ice and bottom Di
(470rrrg of <304.

When 46C1v of nickel peroxide is added and stirred at the same temperature for 10 minutes, it is oxidized to a Pennshannon-type intermediate having stereochemistry and no -. Filter the reaction solution [7, Ren; Wash the O material with methylene chloride + ome, and smother the P solution.

After cooling this furnace liquid with water, methylene chloride containing 38% of tetraethylammonium gyrobidride was used as a reducing agent.
When 5d was added and stirred at the same temperature for 10 minutes, an inversion reaction occurred and a 7β-Schiff-resistant substrate was obtained. Pour the reaction solution into ice water for 20 minutes.
The reaction mixture was adjusted to -15 mg, the organic layer was separated, washed with water, dried with MgSO4, and condensed to obtain 630 grams of the title compound represented by the following formula.

(2) 7β-amino-2α-methyl-3-(1-)′thiru I H-T ) rag-ru 5-ip, ) thiomethyl-1-okyly°-1-dethia 3-cephem-4-carvone Production of Ichinobuenyl methyl ester 630 #/ of the product of the previous section (1) was converted into ethyl acetate lod
was dissolved in Kl, methanol lome containing 290~ of Girard's T reagent was added, and the mixture was stirred for 1 hour in a chamber for 1.8 condensation, resulting in an elimination reaction of k% benzylidene groups from 7β-amine groups.

The reaction solution was stuffed with cotton and the residue was mixed with 20ml of ethyl acetate! The residue was purified by silica column column chromatography (developing solvent pen-vinyl-ethyl acetate (1:I)) to give the title compound represented by the following formula.・Obtain 151ry (35%).

IR(CI(C13), vmaX((:tn')
: 17g5.1720.1602NMR(CDCl2
), δ: 1.57 (3i1.d, J
= 6.8 H7°22m 2 (II3), 2.06 (2H, br, s, amino), 3.82 (3H.

8, Tetrazo-/L I-CI-13), 4.2+
, 4.46 (2H.

ABq, J”= 14 IIz), 4.55
(IIl, d, J = 4.5 Hz.

7-H), 4.86 (IH, q+ J=6.811z
, 2-IT).

5.15 (IIL d, J = 4.511z,
6-J■), 6-92 (In.

II, -CHph2), 7.15-7.70 (I
OH, m, C6H5X2) Example 3 +i+ 7α-pendiamide-2β-methyl-3-(
1-Ethyl-I IT-tetrazol-5-yl)thiomethyl-1-dioxyl-1-der-3-senem-4-
Carvone a2 Novynyl ester ester formation formula % formula % ) ) ) Methyl) azetidin-2-one 2. 'lOg to toluene 2'lOmeK'liJ solution (7, hydroquinone 180W
After adding Tg and heating under reflux for 20 hours under a nitrogen atmosphere, the reaction solution was concentrated and subjected to silica gel column chromatography (developing solvent: benzene-ethyl acetate (4:l)) to obtain the title compound represented by the following formula. 1.sog (gas): J
0 IR(C)IC73), vmaX(cm),
1780. 171g, 166L1600NN
1R(CE13), δ: 1.5+(3
I1. d, J = pm 6-8 Hz, 2Cl13), 3.79 (3I
1. s, Tetrazole I-C1I3), 4.03
．． 4.66 (2H, ABq, J = 14 Hz.

−(J(28−), 4.80(IH, q+ J
= 6.8Hz, 2-H).

4-89 (IH, dd, J = 7.1Hz, 7-H)
, 5.10 (Ill.

d, J = l IIz, 6-H), 6.
85 (IH, d, J=7Hz-C0NH-), 6
-'? 2(IH,s, -C!jph2), 7.10
~8.90 (15H, m, C6TI5X3).

(217α-amino-2β-methyl-3-(1-methyl-I l-l-tetrazol-5-yl)thiomethyl-
Formation of 1-oxa-1-dethia 3-cephemu-4-carphonic acid nophenylmethyl ester 43 mg of PCl3 was converted to methychloride V 724 me
Add 0.48 ml of pyridine at O Cc and stir for 30 minutes at the same temperature. To this reaction solution, 5 rnl of methylene chloride containing the product σ) +200η of the previous section fil was added dropwise at O C and 30 Stir for 1 hour at 0-25°C for 1 hour. Cool again to 0°C and add 12tn of methanol.
A! was added and stirred at the same temperature for 10 minutes at 0 to 25°C for 40 minutes, poured into ice water at 50°C, and after stirring for 30 minutes,
#ii4.

The residue is dissolved in 30 ml of ethyl acetate, washed with saturated v1 water and then with water, dried over MgSO4 and concentrated.

The residue was purified by column chromatography on silica gel (L-hair opening solvent: benzene-ethyl acetate (1:l)), and the result was 5001M of compound ii in Table 1' shown by the linear formula. 7 (50
%).

IR(CHCz'3), νmaX(crn),
177g, 1723. 1608NMR (CDC1
3), δ: 1.49 (3H, d,
J = 6-8Hz.

29m 2-CH3)! 2.00 (211, br, a, amino), 3.77 (3H.

8, Tetrazole I-CH3), 4.04.4.6
3 (2II.

ABq, J = +4 H, -CH25-), 4.
05 (IH, a, J=I Hz, 7 H), 4.
75 (IH, d, J = l Hz, 6) 1).

4.80CII1. q, J = 6.8 Ii
z, 2H), 6.90(:IH,S.

-Cdanph2), '1- IQ ~7.70(1(
H(, m, C6H5X2).

(317α-(3,5-not-tart-butyl-4-hydroxypene solidenamino)-21 termethyl-3-
(1-Methyl-1-tetrazol-5-yl)thimanthyl-I-oxa-1-dethia-3-cephem-4-carboxylic acid Formation of diphenylmethyl ester AiJ Item (21) 350q of 10t+ produced, ゛3.5
-di-tart-butyl-4-hydroxypendialdehyde 184rlwohen M 7100, BeK (jjf
') IIL,, ]) can -5tark installation [j
Heat under reflux for 50 minutes. ! 1! , 2. Then, the title compound 71. shown by the linear formula is obtained. ) 530 mt.

NMR(CI)C/3), (δppm):+
,47(+g■t,a,tort-butyl),l
, 57(3H,'d, J = 6.8JiZ, 2-
CH3).

3.80 (3H, Fl, Tetrazole l -Cll3)
, 4.0g.

4.68 (211, Al3q, J = 14IIz,
-CH25-), 4-71 (IH, br, s,
7-I-I), 4.82 (IIL q,
J = 6-8IIz.

2 H), 5.16 (IH, d, J = l
Hz, 6-H), 5.56(IIl, s,
-OH), 6-90 (In, 3.-C low h2),
7.107.75 (IOH, m, C6H5X2),
7.60 (2TLs, C6IIz).

8.35(Ill, d, J = IHz, -C
I = N -) (4) 7.9- (3,5-di-tert-butyl-4-hydroxybenzylideneamine) = 2β-methyl-3-(1-methyl-I II-tetrazol-5-yl) Thiomethyl-1-oxa-1-
Production of dethia 3-cephem-4-carboxylic acid diphenylmethyl ester.
230 my of MgSO4 and 230 my of nickel peroxide were added under ice-cooling, and I 6 lA1444 m was added at the same temperature.
After stirring, the filtrate was washed with 5 Me of methylene chloride, and the solution F was combined. After cooling this solution with water, 0.1 ml of methylene chloride containing tetodiethyl ammonium borohydride + bmy was added! IO molecule l at the same 1'1%' + degree
J 1 hit, 10 cups of ice water. In this way 7
A position reversal reaction takes place. The reaction mixture is pl+5
・0νCi1. ', l After separating the organic layer and washing with water,
Dry with lVIgsO4 and δ′! Upon reduction, 309 of the title compound, represented by the following formula, is obtained.

C3) 7β-amino-2β-methyl-(1-methyl-I
H-tetrazol-5-yl)thiomethyl-1-oxa-1-dethia 3-cephemu-4-carboxylic acid nophenyl methyl esterProduction of 309+y of the product of the previous section (4) with vinegar MA
5 rne Ic melt screen, Solard T reagent 145 rq
5 ml of methanol containing! Add tF for 1 hour at room temperature
2 Stir and concentrate.

7. Dissolve the residue in 20 me of ethyl bY acid. Wash with water, M
Dry with gSO4 and concentrate.

The residue was subjected to silica gel column chromatography (E i
Purification with Hi i8 -benzene-ethyl acetate (+:I) gives 66rz (31%) of the title compound of the following formula.

in, P-131~133t (minute book 7)
IR (CJICe3), νmax”m-1): 178
3.1720.1602°NMR (CDC/3),
δ: 1.53 (3H, d, ,
T = 6, JH (z.

91m 2-CH3), 2.12 (21L br, s, amino), 3.79 (3H,J tetrazole I-CH3
), 4.02.4.67 (2II, Δilq, J
= 14Hz, -c■r2s-), 4-45(lI
i, d, J = 5Hz, 7-H) 14.80 (
l)1. q, J = 6.811z, 2-
H), /i, '77cII1. d, J = 51
17. , 6-H,), 6.84(11(.

s, CJiph2), 7.10-7.65 (IO
T(, m, C611δX2).

Fruit jji'a U'1111 (1) 7β-(3,5-di-tOrt-butyl-4-hydroxybenzylideneamino)-7α-meth; eC2
Formation of β-methyl-3-(1-tower-11-tetrazol-5-yl)thiomethyl-1-oxa-1-dethia 3-cephyl 4-carvone p7 diphenyl methyl ester The product 53011/ was dissolved in 8 J of methylene chloride and cooled on ice! 14gSO4380m
g, 300rrsy of nickel peroxide was added, stirred for 10 minutes at the same time, filtered, and the filtrate was mixed with methylene chloride 8#+6
Wash with water and add p solution.

Methanol IOme was added to this slurry under ice-cooling, and the reaction was carried out at the same temperature for 30 minutes, resulting in the methoxylation of the 7-position [1'=9
An inversion reaction occurs. When the reaction solution is i+i% fiii,
490 my of the title compound represented by the following formula is obtained.

NMR (CDC, l 3 ), δppm' 1.
33 (3H, d, J = 6d3Hz.

2-CTl3), 1.47(18H,s, ter
t-butyl), 3.5'? C31(,o, -OCH
, +'), 3.80 (3H,s, tetrazole l
CH:>), 4.01. 4.70C2
H, ABq, J = 2 14Hz, --CTI
2S-), /i,'/7(1!1.q, J =
6-8Hz, 2-IT)+5.08(l)T, s
, 6-Ti), 5.59(IH, :%, -0il
).

G,'/IcIII, s, -CHpb2), 7.
10-7.80 (IOIl, muC6Ii5X2)
, 6.66 (2H,s, C5H2), IE, 44
(IH,!1.-crt=N-).

+217. teramino-70-methoxy-2β-methyl-3-(1-methyl-I It-iTorazol-5-
Production of diphenyl methyl ester of 3-7fem-4-carboxylic acid (ethyl) thiomethyl-1-oxa-efdethia 3-7fem-4-carboxylic acid rit: ethyl acid 8-
Add g ml of methanol containing Girard T test tube 240 rv, and stir at room temperature for about 1.5 hours.
Shrink.

The residue was dissolved in ethyl acetate IOmeK, washed with water, and MgS
After drying with O4, it shrinks by 6.

The residue was purified by column chromatography on silica gel (eluent: at/-benzene-ethyl acetate (2:l)) to obtain 24+q (65 g) of the title compound represented by the following formula.

m-p-133~5'e (decomposition) In((JIC13), v (Cm-'):
17g3. 1720. 1600aX NMR (cDcp3) δ: l, 53(
3H, d, J = 6.8I (z.

29m 2- C) I3), 2-16 (2H, br, a, amino), 3.49 (3I"1.s, 0CH3)
, 3.79 (3H,B, tetrazole 1-CH5),
4.03. 4.62 (2H, ABq, J =
14Hz.

-CH2S l), 4.83 (IH, q, J
= 6.8Hz, 2H).

4.85 (IH, s, 6-H), 646 (I
H, s, -CHph2).

7.10-7.70 (IOH, m, C6H5X2).

Actual V115 fi+ 7. α-benzamide-2α-methyl-3-
(2-Methyl-1,3,4-thiazazol-5-yl)thiomethyl-1=oxa-1-dithia-3-cephem-4-carboxylic acid Formation of diphenylmethyl ester (3R,4R)-4-(( IR)-3-(2-methyl-
1,3,4-thiadiazole-5-i A.) 1,000-oh 2-
Oxo-1-methylzolooxy)-3-benzamide-
1.70 g of 1-(+-diphenylmethoxy7carbonyl-1-triphenylphosphoranyritenemethyl)azetidin-2-one was added to Toluev 30 meKfrJFFj L
, 100 q of hydroquinone was added, and the mixture was heated under a nitrogen stream for 10 hours. After concentrating the reaction solution, silica gel column chromatography (developing medium benzene-ethyl acetate (3:
l)), the title compound represented by the linear formula has O.q 5.9 (g + s
).

IR(CHC/3), Sirrr, a, (Cff4-
'): 1784.1719.166L1600.

mmccDct3), δ: 1.4g (3H
,a, ,y = 6.8Hz.

29m 2-CH3), 2.6g (3H,, a, thiadiazole 2-CTI3), 4.3JC2H, br, tl,
-CH2S-), 4.79 (IILq, J = 64H
z, 2-H), 4.90 (IH, dd, J = 8 = 9
．． lHz, 7-H), 5.24(IT(, d, J =
lHz, 6-H), 6-94(II(,s, -
Ctanph2), 7.10-7.85 (15H, m, C
5) 15X3).

Example 6 +I+ 7α-yne zoamy r-2β, 3-dimethyl-1-oxa-1-dithia-3-cephem-4-carboxylic acid diphenylmethyl ester formation (3R,4R)-41(l8)-2 -oxo-1-methylglopoxy)-3-benzamide-1-(+-diphenylmethoxycarbonyl-1-phosphoranylidene meb.
azetidin-2-one l 00 my Zooxane 10me Pressure solution n-11,, After heating under reflux for 52 hours under a nitrogen atmosphere, concentrate 0 The residue is purified by silica gel column chromatography, and the following formula Co 2 CHph 20 my (32%) of the title compound represented by 2 is obtained.

NMR (CDC/3), δppm: 1.42 (
3H, tl, J = 6.811z.

2-cn3), 1.95(3n, s, 3-CI
l:+), 4-32 (IH.

q, J = 6.8Hz, 2-II), 4-'7
4 (Ill, dd, J = 7°1Hz, 7
H) 14.97 (II, d, J = l1lz, 6
-11).

6.90(IIl, !l, -Cppb2), 7°00 = -7,80(15I(, m.

C6H3x3).

(Production of 217α-amino-2i9,3-dimethyl-1-oxa-1-dethia 3-7femu-4-carboxylic acid diphenylmethyl ester) PC161750my was dissolved in 45rne of methylene chloride, and at 0t, added Vilizon l-0at at the same temperature. Stir for 30 minutes at
Add 15d of methylene chloride containing #y dropwise at O 6 C,
It is then pitched at the same temperature for 30 minutes and then at 0 to 25°C for 1 hour.

Cool to 100ml (LC), add 25ml of methanol, stir for 1 hour at the same temperature, stir at 0-25ml for 1 hour, and add 5ml of ice water.
Pour at 0 d, stir for 30 minutes, and then concentrate.

The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and then water, dried over Mg5o4 and stored for 2 hours.

The residue was subjected to silica gel column chromatography (/i7
% INIγi ~ benzene-ethyl acetate (2:l))
Then, 960 square meters (60 units) of the title compound represented by the following formula is obtained.

IR(CHI/3), νmax(cyn-'):
1770* 1718-FJMR(CD(:i
3), δppm: l, 37(3H, d
, J = 6.8IIz.

2-Cn3), 1.84 (2H,s, ll2N-),
1.91 (3H, d.

J = O0'? IIz, 3-CH3), 4
-Of(IIl, s, 7H).

4.35 (1H1q, J-6,8Hz m2
H), 4.72 (IHIs.

6-)I), 6.92(II-r, s, -(J
jph2), 7.10~7.60(forl, m
, C+5H5x2).

(317α-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-2β,3-dimethyl-
Formation of 1-oxi2-1-dethia-3-cephemu-4-carboxylic acid diphenylmethyl ester 6iJ 960 of the product of item (2), 3.5-note
rt-butyl-4-hydroxybenzaldehyde 654
Dissolve the liquid in 50 ml of benzene. L, Dean
Heating and refluxing for 1 hour in a -5 tark apparatus 7, a I
Upon RM, 1500 rQg of the title compound represented by the linear formula % formula % is obtained.

IR(CII(:/!3), νrllJLX(cy
-'): 1770.171'L 1680°NIV
'pt (CD C13), δppm:
1.41 (3T(, d, J = 6. δII
z*2-Cl-13), 1.46(18IL!L
, tert-+3u), 1.97 (311°d,
J = 0.9I(z, 3-CH3), 4.44
(IIl, q, J = 6-8Hz, 2-H),
4.70 (IH, br, s, 7-H).

5.13 (IH, br, s, 6-H), 5.5
8(IH, II, -0)I).

6-90(IILs, -CHph2),'/,1
0-7.70 (IOH, m.

C6H5X2), 7.64(2H,1,C6H2),
8.41 (IIl, d, J=I, 5Hz,
-CH=N-).

(4) Production of 7β-(3,5-di-tert-butyl-4-hydroxybenzylideneamino)-2-9,3-dimethyl-1-mexar-1-dethia 3-cephem-4-carboxylic acid diphenylmethyl ester ( 1400 mg of the product 3) was dissolved in 30 ml of methylene chloride, and Mg5 (14950 mW,
Add 950 g of nickel peroxide, stir for IQ minutes at the same temperature, filter, wash the V3 filtrate with 30 ml of meglychloride, and combine the liquids.

After cooling this r liquid to -20t, methylene chloride containing 100mg of tetraethylammonium borohydride was added to 2m/! was added, stirred for 10 minutes at the same temperature, and poured with ice water at 50°C.
Please give me a number.

The reaction mixture was adjusted to pH 5.0, and the amorphous layer was separated.
After washing with water, drying with MgSO4, and concentrating for 1'', 1200 ml of the title compound, represented by the following formula %, was obtained.

(5) Production of 7β-amino-2β,3-zomethy/l/-1-oxal-1-dethia-3-cephem-4-carboxylic acid diphenylmethyl ester +200 # of the product of precursor (4) was added to Egul acetate 14
m/! Dissolve the mixture, add 14 ml of methanol containing Girard's reagent, and incubate at room temperature for 1 hour.
Stir and reduce by 4 times.

The residue was dissolved in 45 ml of ethyl acetate, washed with water, and MgS
Dry with O4 and concentrate.

The residue was purified by column chromatography on silica gel (developing solvent benzene-ethyl acetate (1:I)) to obtain the title compound 488-(64) represented by the linear formula.

IR((JIC/3), νmax(RIm-'
): 1778. 1718NMR (CDI
:/3), δpp+n: 1.41(3H,
d, J = 6.8Hz.

2 C113), 1.84 (211,br,
s, Tl2N), 1.9 g (3H.

d, J = 0-9TTz, 3-
CH3), 4.40 (I D1.q, J=6
．． 8Hz, 2-IT), 4.45 (IIL d, J
= 4.0Hz, 7-TT), 4.98(IIL
d, J = 4.0Hv, 6-H),
6.89 (Jft, s, -CHph2), 7-
IQ ~7.60 (IOH, m, C61 (6X2).

Example 7 (1) 7α-pen cyamide-2α,3-dimethyl-1
-Oxa-1-・Dethia 3-cephemu-4-cardine Diphenyl methyl ester raw material 52 (3rt, 4R)-4-((IR)-2-okino 1-
Methylpropoxy)-3-penguamido-1-(+-diphenylnotoxylponyl-1-phosphoranylidenemethyl)a-binazin-2-onto30! j toluene +
Add molten M12 and Pydrokino 77Q my to 20d, heat reflux for 40 hours under Mengsu air, and then condense.

The residue was purified by glass chromatography on each silica column to obtain 0.43.9 (52%) of the title compound represented by the following formula.

IR (CIIC/3), ymax (tm), 1
770. l'71g, 166ONMR (CDC/3
), Jppm: 1.3 & (3H, d, J
= 6-9Hz.

2 CH3), 2-02(3I(,a, 3
- CH3), 4.42 (IH.

q, J = 6.9Hz, 2-H), 4.99
(IH, dd, J = 7.6.1llz, 7 H
), 5.13 (IH, s, 6 H).

6-91 (IH, 11, -CHph2), 7-00~
7.90 (15H, m.

C6H5X3).

(2) Production of 7α-amino-2α,3-dimethyl-1-oxa-1-dethia 3-cephem-4-carboxylic acid diphenylmethyl ester PC/'s 1720 H9 was dissolved in methylene chloride AOtt and 0°C So pyridine 1. Add Omg and at the same temperature 3
Stir for 0 minutes, add dropwise at 0°C, stir at the same temperature for 30 minutes, and further stir at 0 to 25°C for 1 hour. Cool again to θ°0.
Add 25 tne of methanol and incubate at the same temperature for 1 hour.
Pour and stir at 5°C for 1 hour, pour into ice water 40°C, stir for 30 minutes, and concentrate.

The residue is dissolved in 50 ml of ethyl acetate, washed with saturated aqueous sodium bicarbonate and then water, dried over Mg SO4 and Q-condensed.

The residue was subjected to silica gel column chromatography (I
Purified with M open solution H benzene-ethyl acetate (2:I),
1035 mg (66%) of the title compound is obtained.

IR (CHC/3), ymax (crn)
: 1773. 172ONMR (CDC/3),
Jppm: 1.40 (3) 1. d, J
= 6.9Hz.

2-CH3), l side g(2H, br, s, -N
H2), 2.0f (38°s, 3-- CH3), 4
．． 02 (IH, br, s, 7-H), 4.37 (IH-
q, J = 6.9Hz, 2-H), 4-
81 (IH, br, s.

6-H), 6-93(IH,II, -C)I
ph2), 7.10 to 7-60 (IOH, m, C6
H6X2).

(3) 7α-(3,5-di-tert-butyl-4-hyF'o-t' dibenzylideneamino)-20,3-dimethyl-1-oxa-1-debouar 3-cephemu 4
-Formation of phosphoric acid nophenyl methyl ester (100 OWv of the product from the previous section (21), 3. Dissolve 680 ~ of 5-di-t@rt-butyl-4-hydroxypendyldehyde in 50 ml of benzene 1K, Dsan-
The mixture was heated under reflux in a 5 tark apparatus for 1 hour and condensed to give 1571 da of the title compound.

IR (CHC/3), ymax (ci-'):
1775. 1720. 1682°NMR (CDC
13), Jppm: 1.40 (3H, d, J =
6.9Iiz.

2-CH3), 1.46(18H,s, tart
-Bu), 2.05 (3H.

s, 3 CH3), 4.43 (IH, q, J
= 6.9Hz, 2-H), 4.68(IH, br
, s, 7H), 5-27(IH,a, 6H
), 5-57(IH,s, -0H), 6.92(
IH, II, -C, qph2) 7.10 to 7.70 (
IOH, m, C6115x2), 7.60 (2H,
a.

-C6H2), 8.41 (IH, d, 1.5Hz,
-CII=N-).

(4) 7-noter (3,5-tert-butyl-4-
Hydroxybenzylideneamino) = 2α, 3-tumethyl-1-oxa-1-dethia 3-cephemu 4-carvone 1! iJ Production of diphenyl methyl ester 150011Pg of the product of the previous section (3) was dissolved in 30ml of methylene chloride. Under ice cooling, MgSO4970~ and nickel peroxide 970Fnt were added, and after stirring at the same temperature for 10 minutes, Wash the filtrate with 30 d of methylene chloride and combine the p solution.

After cooling this P solution to 20 cc, add 2 ml of ichmethylene salt containing tetraethylene/l/ammonium boronolide IIOmy, stir at the same temperature for 10 minutes, and pour into 50 ml of ice water.

The reaction mixture was adjusted to pl (5.0), washed with water, dried with MgSO4, and concentrated.
1400 rrv of the title compound of formula t-Bu is obtained.

(5) Production of 7β-amino-2α,3-dimethyl-1-oxa-1-dethia 3-cephemu-4-carboxylic acid diphenylmethyl ester 14001 rq of the product of the previous section (4) was converted into ethyl acetate A/
15 ml of methanol containing 690y of Girard T reagent dissolved in I 5 tIg is added, stirred at room temperature for 1 hour, and concentrated.

The residue was dissolved in 50 tut of ethyl acetate, washed with water and MgS
(Concentrate after drying with M.

When the residue was purified by silica gel column chromatography (developing solvent: benzene-ethyl acetate (1:I)),
s 87 rnq (6(, %
).

IR (CHC13), ymax (on):
1782. 171? , 1600°NMR (C
DC/3), δppm: 1.44 (31
−1,d, J = 6.9Hz.

2 CH3), 1. B6(2H,br, 1
．． -NH2), 2.04(3)1゜s,' 3-
CH3), 4.44 (In, q, J = 6.
9Hz, 2-H), 4.49(l)L d,' J
= 3.8) 1z, 7-T(), 5-13(II
l, d, J = 3.8Hz, 6H
), 6.90 (Ili, 1-C!!plt2)
, 7-IQ ~7.70 (IOII-m, C6)1
δX2).

Example 8 +11 7α-benthiakybi 2α-methyl-3-chloromethyl-1-oxa-1-tethia-3-senoem-
4-Cal? 59 g of azetidine-2-ontyl ester was dissolved in 50 t of toluene for 17.3 hours, and after refluxing from 1 to 9 condensed, the residue was poured into a silica gel column. Chromatography (f
Purification with fA61 solvent Hensen-ethyl acetate (5:l) yielded 0.70 g (68 g) of the title compound of the following formula fx,
#'Jru0IR(cHc13), νn1ax(crn-')
: 1786.172L 1663°1602°NMn (CDCI 3), δ: l-46(
3H,d, J = 6.9Hz.

99m 2-CH3), 4.22.4.53 (2H, ABQ
, J = 11.5Hz.

-CTISICe), 4.78(In, q, J
, = 6.9H7,, 2-Ti).

4.95 (IH, dd, J = 7.5.1■iz,
7-H), 5.23(IH, d, J = lH
z, 6-)1), 6.95(I)i, s.

-Ctanph2), 1-00~7.90(15I(, m
, C6115X3).

(2) 7α-benzamide-2t1-methyl-3-(,
I+ 3r 4-thiadiazol-A・-5-yl)thiomethyl-1-maker 1-dethia 3-cephem-4
- Cal 7I? 7! Formation of 4e nophenyl methyl ester fflil 800 μ of the product of item (1) was dissolved in 20 dK of methylene chloride, 5-mercapto-1,3,4-thiadiazole 220 Q Na'HCO326077 g, tetraethylammonium chloride 'i Q Add an aqueous solution containing Tnf (9 liters) and incubate for 2 hours at room temperature. Separate the organic layer, wash with water, dry and concentrate, and transfer the residue to a 5 liter silica column column chromatogram). Benzene-acetic acid: r-thyl (3: I)) f3'i
',! In other words, the crystal of the title compound represented by the following formula s s
o rny (63fj) is obtained.

m-p, 170-172 c'C (min 9y) IR (C
)I+]/! 3), l'(c7n-'):
1782. 1718. 1665°aX +600°NMR (CDC/'3), δppm: 1.
52 (3I1.d, J = 6.8Hz.

2-CH3), 4.41(2H, br, s,
-CH2S-), 4.82 (IH, q, J = 64
) Iz, 2-H), 4.90 (IH, dd.

J=7. IHz, 7-H), 5.26 (IH, d, J=
IIIz.

6-H), 6.96(IH,s, -Ctanph2
), 7.06 (IH, d.

J = 7. lHy,, -CONH), 7.10~
7.90 (15H, m.

C6H5X3), 8.96 (IH,yl, Thiadiazole-AI2-H) Reference Example 1 +11 (3R,4R) -4-((I R) -1
-ethoxycarbonylethoxy)-3-benzamide-
1-(+-diphenylmethoxycarbonyl-2-methylglob-1-enyl)azetidin-2-one (compound a
) and (3R,4R)-4-((+S)-+-ethoxycal Δ?nilethoxy)-3-benzamide-1-(1
-diphenylmethoxycarbonyl-2-methylgulo7'
-1-enyl)azetidin-2-one (compound b) (step A) (I
R,5S)-3-phenyl-6-(1-diphenylmethoxycarbonyl-2-methylpros-1-enyl)-7
-oxo-4-oxa-2,6=diazabicyclo[3,
2,0]hept-2-ene (Journal of C
chemical 8o1@ty, Parkln L
10 g of DL-α-lactate ethyl/l/ester represented by the following formula (where Me is a methyl group and Et is an ethyl group).
meVC1, trifluoromethanesulfonic acid 0.
After adding 5 re and stirring at room temperature for 1.5 hours, a condensation reaction of the raw material compound (r) takes place. “vulgar”
The aqueous layer was removed, and the resulting oil was dissolved in ethyl acetate for 70 minutes.
Dissolved in MgS, washed with saturated saline, then water with MgS.
Dry with O4 and concentrate.

The residue contains the two (1σ) heriastereomer obtained as a product, and these were purified by column chromatography (developing solvent 0'A benzene-vinegar 6).
Separate with ethyl (7:1) and ethyl ether solution.
When crystallized, the following formula % is obtained:
(+-nophenylmethoxycal H?nyl-2-methylnorono-1-enyl)azetidin-2-one (compound R)
2・1μ and the following formula % formula %) Ethoxycarbonylethoxy)-3-benzamide-1
-(+-diphenylmethoxycarbonyl-2-methylglob-1-enyl)azetidin-2-one (compound b)
Obtain 2.o5g.

Physical properties of (compound a): ”・p, 104-6°C [α]D-75° (C1, o, C] Icl!3) 60
2 Physical properties of (compound b): m-p, 133-5t [α]D2.1' (c 1.O, CHCl3)IR
(CHCi1!3), ν□38 (釧-'): 17
6L 1735.166L 600 f21 (3n, 4 R)-4-((I R)
Production of 1-ethoxycarbonylethoxy)-3-benzamido-1-(1-nophenylmethoxycardenyl-1-hydroxymethyl)azetidin-2-one (Step B
10th step C) Dissolve 5.C9 of compound (b) obtained in the previous section (1) in methylene chloride at 150 meK. At -60°C, ozone is passed through the solution while keeping the solution on the back. This results in compound (b)t, J
It is converted into compound (e) of the following formula. (Regarding the applicant/l'&
(See WfL Specification No. 198466, Reference Example 1 (a) (lv)). To the reaction solution containing this compound (c), 1 g of zinc powder and 1 ml of acetic acid were added at -60°C, the temperature was raised to 0°C, and again at the same temperature, 10 g of zinc powder and 1 ml of acetic acid were added.
0. Add p and stir for 30 minutes.
- After this reaction mixture was filtered, the P solution was washed with saturated distilled water and then with water, dried over MgSO4, and then subjected to the θ phase. ! ? (90%).

+3+ (3R, 4R) -4-((l R) -I
-ethoxycarbonylethoxy)-3-benzamide-
Production of +-(+-zobuenylmethoxycarbonyl-1-chloromethyl)acetinon-2-one (Step D) Song order (
4.5F, g of the product of No. 21 was added to 50 ae of methylene chloride.
After dissolving K and cooling with water, add 38 g of pyridine I and 2.08 g of thionyl chloride, and stir at the same temperature for 30 minutes to turn the mixture red.

Pour the reaction solution into ice water, wash with organic R-cold separation I7, saturated sodium bicarbonate solution, and then water 1-, dry with MgRO4, and confuse;
Then, 4°so of the title compound represented by the following formula % formula %,! Obtain i' (9s%).

t4)(31,4R)-4-((lR)-l-ethoxyrudenylethoxy)-3-penzamyl'-1
-(+-nophenylmethoxycarbonyl-1-triphenylphosphoranylidenemethyl)avitinon-2.-one production (Step E) 45.9% of the product of the previous section (3) [''T7 form 50
Dissolved in me, triethylamine 1.46 □e, triphenyl 7tosufine (PHpb3) 4.5, q
was added, and the mixture was stirred at room temperature for 1.5 hours to form a disulfonylidene. Pour the reaction mixture into 50 dK of ice water, adjust the pH to 3, adjust the diameter, and separate the layers. Wash the organic layer with saturated sodium bicarbonate water, then water, dry with MgSO4, and concentrate. Developing solvent benzene-ethyl acetate (3:l):
E-purification yields 4.5 g (7195) of a compound of the following formula.

xR(c■xc13), νmaX(Cffl)
, +764.1732.1652゜612 +51 (3I4,4 R) -4-((l R)
-1-carboxyethoxy)-3-benzamide-+
-(+-diphni:nyl-1-tri7ethyl;r-sphoranylidenemethyl)azetidine-2
- Production of cod (Step F) Reaction 155 of the previous section (4). 4.50g of stuff with Fusetone 70g
ml, 23 ml of water, 5.7 m/! of IN-NaOH aqueous solution! was added and stirred at room temperature for 2 hours.Furthermore, I N -NaOII aqueous solution 2. FSml! Add and continue to hydrolyze at room temperature for 30 minutes with stirring.

After adjusting the reaction solution to pH 7 and OK, concentrate, powder the residue with isopropyl ether and take it off. This powder was suspended in a mixture of 50 ml of ethyl acetate and 50 ml of water, and adjusted to pH 2 under cooling with water. After adjusting to 0, the organic Jg,'i is separated, dried with MgSO4, and then fed, it is possible to obtain (96) of the title compound represented by the following formula: +6+ (3R,
4R) -4-((l R) -3-(!-Methyl-I
N-tetrazol-5-yl)thio-2-millionxo 1
-Methylpro)”? xy)-3-benzamide-1-(
+-Diphenylmethoxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one production (step a + n rr +, y) m 3.2911 of the product from the previous section (5) was dissolved in methylene chloride 40 me Ic '18 M, -10cc TeN
0-51 mg of Chilmo #hon'J and 0.45 mg of ethyl chloroformate (C1-C00Et) are added and reacted at the same temperature for 30 minutes with 44 hours of stirring to produce a compound of the following formula. To the reaction solution containing this compound, 10 mg of ethyl needle containing 8 mmol of diazomethane was added dropwise while cooling with water, and after the dropwise addition, the mixture was stirred at the same temperature for 30 minutes to cause a diazomethylation reaction, which was expressed by the following formula: CQ2CHph2 (3R,4B)- 4-((IR)-3-diazo-2-oquinol-1-methylproboxin)-3-pendzamido-1-(+-diphenylmethoxycarbonyl-
A solution of 1-triphenylphos7traniIJdenmethyl)azetidin-2-one is obtained.

(11) This solution K6. ) 1-IICE cycloxane solution (1.43 d) was added to a water-cooled bottom, and the chlorination reaction was carried out under stirring for 30 minutes (r').
Separate the organic layer, wash with saturated sodium bicarbonate solution, then with water, dry with Δ4gSO4, and concentrate.
)) Denmethyl)azetidin-2-one 3-10. ! i'O is obtained as an oil.

(liD) This oil was dissolved in 59trtK of methylene chloride, 0.60.p of 1-methyl-5-mercapto-IH-tetrazole and 1ml of pyridine ch4 were added, and the mixture was reacted with stirring at room temperature for 15 hours. (1-
A direct extension reaction is carried out with the methyl-tetrazol-5-yl)thio group. Pour the reaction solution into 50 ml of ice water. Separate the organic layer and wash with saturated sodium bicarbonate solution and then water.

After drying with MgSO4 and shrinking by 6 units, the residue was purified by column chromatography on silica gel (developing solvent: penze/-ethyl acetate, C2: l), resulting in the following formula: % 5-yl group) The title compound, i.e. (3R, It, R) -4-((I R) -3-(
1-Methyl-I I'! -tetrazol-5-yl)thio-2-oxo-1-methylpropoxy)-3-penduamide-1-(+-shifuconinylmethoxycarbonyl-
1-triphenylphosphoranyritenemethyl)azetidin-2-one 2.05. Obtain f (s6 width).

IR(C)IC/3), v (cm-1):
1766, 1730. 1653゜ax 615 Reference Example 2 (1) (3B,4R)-4-((Is)-1-ethoxycaryl+'nylethoxy)-3-henso7 mido-
Production of 1-(1-J phenylmethoxycarzenyl-1-hydroxymethyl)azetidin-2-one 3.0 g of compound (a) obtained in Section (1) of Reference Example 1
methylene chloride + 50 rn/! Dissolved in -6oc
C: Pass ozone through until the solution turns blue. Add 1.0g of zinc powder and 1ml of acetic acid to this at 00C.
At the same temperature, 6.8 g of zinc powder and Fi +
Add 6.3 ml of acid and stir for 30 minutes.

The reaction mixture was filtered, and the filtrate was washed with 70% saturated sodium bicarbonate water and then with water, dried over MgSO4, and concentrated to give the title compound with the following formula: % 2.75. Obtain V (Article 96)0 In(CIICl3), νrnax (cm)
, 3420. 1781. 1735°+660.
1600°Nrt4R (CDCJ3), /'ppm: 1
．． IL 1.21(3H,t, -CH2-Ct13
), L18. 1.4 to 3) T, d, -CII
CII3), 4.03°4.12 (2H, q, -
C-I! 2CH3), 4.33. 4.43 (IH
,q.

-(2TTC□H3), 4.75. 4.80
(IIT, dd, 3-If),
4-90°4, '79 (IH, d, 4-H), 5,4
0.5.53 (IH, br, s.

-C, qOH), 6.86.6.92 (IIL 1
1. -Cpph2), 7.60 to 7.80 (15T1
．． m, C6H5X3) f21 (3R, 4
I? )-4-((Is)-l-ethoxylponylethoxy)-3-penzamide-1-(+-diphenylmethoxycarvinyl-1-chloromethyl)azetidine-2
- Production of 2.75 g of the product from the previous section (1) in 50 ml of methylene chloride.
6, and after cooling with water Bi' +1 Gint 24,! 7,
Add 87 g of cyclized thiol and stir at the same temperature for 30 minutes.

After washing with soda water and water, inverting with MgSO4 and concentrating,
2.64 ji ('73%) of the title compound is obtained.

IR(CHe13), shi,n,x(,M),
1785.173L 16661605 NM1't(CDC13), δppm: I, 2
2(3H,t, -CH2Cs3).

1.37.1.47 (3H, cl, -CdanCH3),
4.12 (2T1.q.

-C tool 2cH3), 4-44 (IH9 (11-hit C!)
I3), C73 (In.

dd, 3H), 5.32. ,．． 5.37 (IH
, (1,4H).

6.17.6.21 (lH2s--CIICl), 6
J'1.6.92 (IH.

s, -CIIph2), 7.10-7.70 (1
5)1. m, C6H, 5X3).

(31(3R,4R) -4-((I S ) -1-
Ethical? Formation of Nylethoxy7i3-Benzamido-1-nophenylmethoxycarbinyl-1-triphenylphosphoranylidenemethyl)'azetidin-2-one 2.64 g of the product of the previous section (2) was dissolved in 50 d of chloroform.
Dissolve 0.15 mQ of triethylamine and 2.75 g of triphenylphosphine at a force of 15E.
I hit J45z. In the reaction -'a: 4<"X-,
-+ Ome With LC, after adjusting the pH to 3.0, separate the liquid into 1 Sakura r: +y, wash with #+p, '

When purified by column chromatography (developing solvent: benzene-ethyl acetate (3:l)) using a column of distilled liquid, 2.50.9 (67%) of the compound in Table 131 with the following formula % was obtained. I want to take a look.
IR(CHe73), sim, x(trn-'):
1761.1739.1655°615 (4) (3R,4R)-4-1(Is)-1-carboxyethoxy)-3-penzamide-1-(+-diphenylmethoxycarzanyl-1-) I7 phenyl Product of phosphoranylidenemethyl)azetidin-2-one 611 term + 3): , ', 50.9 to acetone 3
'Dissolve 7ml VC, l2ml water, lN
Add 3-16 mp of NaOH aqueous solution, stir at room temperature for 2 hours, and add 1.6 ml of I N -NaOH aqueous solution! Add and stir at room temperature for 30 minutes.

7 After adjusting the reaction solution to pj+ 7・O, it is condensed, and the residue is powdered with IpE and poured into a container◎ Mixed solution of 7 ethyl acetate 50 ml water 50 cl 11
t1 suspension 7: i3 L, after adjusting to pjl 7.0 under ice cooling,
When the 13"5 layer is separated and condensed by drying, the title compound of the following formula is 2., 28 j' (q s
%).

In(CIICl3), Sim, x(ctn)-1
765,1730,1658゜l617 f5) (3R, 4R)-4-((,l S
)-3-(1-methyl-I II-tetrazole-5-
yl) Chihiki-2-oxo-1-methylfuropoxy)-3
-Production of benzamido-1-(+-diphenylmethoxycarvinyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one
After 5 m, 0.36 m of N-methylmorpholine and 0.29 m of ethyl chloroformate were added at a melt angle of t (L, -10 cc), and the mixture was stirred at the same temperature for 30 minutes.

Muether lome containing 5.5 mmol of noadimethane was added to the reaction solution under water cooling, and at the same temperature for 30 minutes (1. -I-methylpropoxy)-3-benzamide-1-(+-diphenylmethoxycarbonyl-1-
Triphenylphosphoranylidenemethyl)azetidine-2
A solution of -on is obtained.

Add 6N-1-ICI dioxane FJ solution 0- to this solution.
91 me was lowered to the water-cooled lower part, and held at the same temperature for 30 minutes.
Open 30ml of ice water for 1K. Arisugi waste filter 7 liquid 11, saturated sodium bicarbonate solution 1, washed with water 12, dried heat with Mg So 4 and condensed 2゛l each time (3R, 4R) -4-((l S )
-3-chloro-2-oxo-1-methylpropoxy)
-3-Benzamido-1-(,1-,;,'phenylmethoxycarbonyl-1-triphenylidenomethyl)azetidin-2-one 2.05jJ is obtained as an oil.

Add 1,1-methyl-5-mercapto-I H-tetrazole 0.32I to 2Qml of methylene chloride.
, pyridine (L26r/!) was added, stirred at room temperature for 15 hours, and poured into 20 ml of ice water.

4,1: Separate the e layer, wash with saturated Hf water and then water, and continuously feed with 1-.8 gsO4 after heating.

The residue was washed with silica gel (7'f).
Ifk ill m medium benzene-acid resistant Egur f2:
l)) De Sei! , lJ, then the title compound, ie! =
(3rv, 4R)-4-((ls)-3-(,1-
Methyl-I H-tetrazol-5-yl)thio-2-
Suquino-1-methylpropoxy)-3-benzamide-
1-(+-synenylmethoxycardenyl-1 to I7
Phenylphosphoranylidenemethyl)azetidine-2-
On L70,? (72%).

IR(CIIC/3)-ν(r, tz+-')
: 1765.1735.1658°ax 619 Reference example 3 +11 (3R, 4R) -4((l R) -3-
Noacy 2-oxo-1-methylpropoxy)-3-penzamide-1-(+-diphenylmethoyacical 7)
? Production of nyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one 3.29 g of the product of item (5) of Reference Example 1 was mixed with 40 ml of methylene chloride, and -+o'u DeN
-Methylmorpho IJ 70.57 me, process 0.45ml of ethyl chloroformate and stir at the same temperature for 30 minutes.This reaction solution contains 8 mmol of diazomethane.
Add 0.0 ml of acetic acid to a water-cooled bottom, stir for 30 minutes, add 0.23 ml of acetic acid, and stir at the same temperature for 30 minutes.Pour the reaction solution into ice water, separate the organic layer, and add saturated sodium bicarbonate. Wash with water, then dry with MgSO4, and then ff'1m.

Remove the residue using silica gel column chromatography (developing solution: 4·v benzene-ethyl acetate r3:l). m
Then, 2.91. of the title compound of the following formula. ! Get a score of 9 (section 86).

IR (CHC43), ν (ti'): 2110
．． 1763.1655゜ax 618 (21(3R,4R) -4-((l R) -3-chloro-2-oxo-1-methylpropoxy)-3-benzamido-1-(1-zienylmethoxycarbonyl −
Production of 1-triphenylphosphoranylidenemethyl)azetidin-2-one 2.91.9 of the product from the previous section (1) was added to 4° of methylene chloride, and 6 N -I (el , Z dioxane solution 0-92s+/! was lowered under ice cooling, and at the same temperature
Stir for 30 minutes at room temperature and some in ice water.

Aribayashi'! The layers were separated, washed with saturated sodium bicarbonate and water, and the Mg
After drying with SO4 and concentrating, 2.73 g (93%) of the title compound of formula % is obtained.

IR(C)Ie13), pm, X(crn),
+765. 1742. 1650°618 +a+ (311, 4F, ) -4-((I R)
-3-(2-methyl-1,3,4-guadiazol-5-yl)thio-2-oxo-1-methylpropoxy)-3-benzamido-1-(+-diphenylmethoxycarbonyl- 1-) Production of I+phenylphosphoranylidenemethyl)azetidin-2-one 1.76 g of the product from the previous section (2) was mixed with 30" methylene chloride.
VC bath 81 L2.2-methyl-5-mercapto-1
゜3.4-thiadiazole 0.35g, pyridine 0.2
Add 6ml and stir for 151.1 minutes at constant temperature, then add 30ml of ice water.
Open it in le.

The organic layer was separated, washed first with saturated sodium bicarbonate solution and then with water, and the Mg
After drying with SO4 and concentrating, the residue was purified by column chromatography on silica gel (developing solvent: benzene/ethyl (2:I)) to give the title compound at 1.40%. Get '7 (71g).

IR(CIIC/3), νmax CCm)
, +763. 1737. 1652°615 Reference example 4 m (3R,4R) -4-((I s ) -l-
carboxyethoxy)-3-benzamide-1-(1-
Nobudinylmethoxycarbonyl-2-methylnoloboo 1
-enyl)Azenano/-2-one Compound (a) 6.10 obtained in Section (1) of Reference Example 1
Dissolve 70rneVc of acetone and cool with water 30ml of water containing 470ml of sodium hydroxide/! and then at the same temperature for 1 hour, and then at room temperature for 1 hour. After distilling off the acetone, wash the resulting aqueous solution with ether, then acidify (pH 2, O
) and extracted with ethyl acetate.

The organic layer was dried with MgSO4, concentrated, and extracted with ether
1? 5.30 of the title compound when converted into a product. '/(91 width).

m, p, 172-174 c'C (decomposition) IR (CII
C73), v (Cm-'): 1775.
1724. 1660°ax +605°NR=IR(CI)Cj'3), δppm: 1
．． 40 (3H, d, J = 6-8Hz.

-CIICII3), 2.01(3H,s, heCH
3), 2-23 (37(, s.

= CH3), 4.41 (IH, q, J = 6-
811y,', -CdanCH3).

4.75 (IH, dd, J = 6. lT■z,
3-H), 5.14 (IH.

s, 4-H), 6. rS2(IT(,s, -c
trph2), 6-90 to 1-80 (15H, m,
C6T (5X3).

(21(3R,4It) −4−((+s) −
3-Diazo-2-oxo-1-methylpropoxy)-3
-benzamide-1-(1-diphenylmethoxyal 7
P-nyl-2-methylprop-1-enyl)azetidine-
Formation of 2-one 5・oofI, the product of the previous section flll, was dissolved in methylene chloride 70
Dissolve N-methylmorpholite at -10°C in 71.
19me, chlorgibutyethyl (L 96 rrt '4
Add j' and stir for 30 minutes at the same t% concentration. To this reaction solution, 40 ml of muethyl ether containing 18 ml σ] diazomethane was added dropwise under water cooling, stirred for 30 minutes, and 0.57 pi of acetic acid was added. After stirring for 10 minutes, pour into 100 ml of ice water.

The amorphous layer was separated and washed with ξ1210 sodium bicarbonate solution and then with water.

If we reduce the equation by 1, then the following equation 5.15 g of the title compound are obtained.

IR (CC14), νmax (z-'): 221
0.1775.1722°1660.

NMR (CDCl3), δppm: 1.32
(3H, d, J = 6.8Hz.

-cucH3), 2-07(3H,!1.HeCH3
), 2.28 (3H, II.

4.83 (In, dd, J” 7. lHz,
3-11), 5-04 (IH, d.

J = IHz, 4-II), 5.30(I
H, @, -CFIN N2), 6・88 (IH, n
, -cdanph2), 7.10-7.85 (151(
,,m, C6H5X3) (3+ (3R, 4R) -4-((+s) -
3-chloro-2-oxo-1-methylpropoxy)
-3-Benzamido-1-(1-sophenylmethoxycarbonyl-2=methylprop-1-ene/L)azetidin-2-one 5I of the product of the previous section (2) was dissolved in 50 ml of methylene chloride.
K ffj solution L, after ice-cooling, IN -HC/dioxane solution 9- was added dropwise, poured at the same temperature for 30 minutes, and after stirring, ice water 50
Pour into ml.

The organic layer was separated, washed with saturated type 1 water and then with water, and dissolved in MgS
Concentration on a dry edge with O4 yields 5.10 g of the title compound of formula:

I R (/3 to CI); νmFLx (tFI+-
'): 1772.1723.1663°603 hm (CDC/3), δppm: 1.34 (3H,
d, J = 6.81 (z.

-C) TCC50, 2,0,4 sounds, 3H,s,'-
CI! 3), 2.2'B3H,I.

-\CH3), 4.05(2H,n, -CH2Cl
), 4.27 (IH, q.

J = 6-8Hz, -CIiCII3), 4.7
8 (IH, dd, J = 7.1Hz, 3-H)
, 5.06 (IH, d, J = IHz, 4-
H).

6.88 (IH, s, -CHnh2), 7.00~
7.90 (15H, m.

Cl5)I5X3).

+4+ (3R, 4R) −4−((ls) −
3-(1-Methyl-I Tl-tetrazol-5-yl)thio-2-oxo-1-methylpropoxy)-3-benzamido-I-(+-diphenylmethoxycarbonyl-2-methinophrogur-1-enyl) Azetidine-2-
5.10 of the product of the previous section (3). p is methylene chloride 50
1-Methyl-5-mercapto-I
II-tetrazole 1.06 l, pyridine 0.9 m
After stirring at room temperature for 15 hours, the mixture was added to 50 mg of ice water.

The organic layer was separated, washed with saturated sodium bicarbonate solution, then water, and MgS
Dry with O4 and concentrate.

The residue was subjected to silica dal column chromatography (7i1
II Solvent Hensen-ethyl acetate (3:l) a)
1, the title compound of the following formula % formula % 5-16,! i'('89%) obtained.

IR (CHC/3), νmaz (crn-'):
1773.172511665°1605.

NMR (CDC/3), δppm: 1.3
5 (3H, d, J = 6.CH2゜-CHCdan3)
, 2-20(311,l-\el13), 2.28
(3H, s.

to CH3), 3-86(3H,s, tetrazole 1-
CH5).

4.22(2I1.8.-CH2S), 4,37(
IIl, q, J = 6-gHz, -CdanCH3
), 4.83 (IIl, dd, J = 6.l
Hz, 3-H), 5.21 (IH, d, J =
IIIZ, 4-It), 6.86 (IH,s,
-CHph2), 7.00 to 7-80 (1511,
m, C6H5×3).

+5+ (3R, 4, R) -4-((+s)
-3-(1-methyl-IH-tetrazol-5-iA)
thio-2-oxo-1-methylpro4xy)-3-benzamido-1-(+-diphenylmethoxycarbonyl-
Formation of 1-hydroxymethyl)azetidin-2-one (3R,4R)-4-((IR)-3-(1-methyl-
IH-tetrazol-5-yl)thio-2-oxo-1
-methylpro4xy)-3-benzamide-1-(+-
Diphenylmethoxycarbonyl-2-methyA7'log-1-enyl)azetidin-2-one 2.oog was dissolved in methylene chloride Some, and at -60 cc the solution became π-colored:/
Ozone is conducted until C.

Add to this -60cc of lead powder 0.40g and acetic acid 0.4m
Add zinc powder, raise the temperature to 0°C, and add zinc powder again at the same temperature.
・Add 98y acetic acid 3.60- and stir for 30 minutes.

The reaction mixture is filtered, the solution is washed with saturated sodium bicarbonate solution and then with water, dried over MgSO4, and condensed to yield 1.10.9 (57%) of the title compound of formula %.

IR (CHC/3), νmax (”), 34
00. +776, 1740°1664, 1604 +61 (3R, 4R) -4-((l s
) -3-(・1-Methyl-I H-tetrazol-5-yl)thio-2-oxo-1-methylpro-4xy)-3-benzamido-1-(I-diphenylmethoxycarbonyl-1-chloromethyl)azetidine -2-one production 1.38 g of the product of the previous section (5) was added to 40 y of methylene chloride.
Ki solution, pyridine 0.53me thionyl chloride 0 under ice cooling
・Add 48ml and stir for 15 minutes.・Pour into 50ml of ice water.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, then water, and MgSO
After drying over 4 ml and concentrating, 1.21.9 (63 width) of the title compound of the following formula is obtained.

IR (CIICJ3), v (Cm-'):
17g9.1752.1663゜ax +603゜+71 (3R, 4R) -4-((+s) -
3-(1-methyl-I H-tetrazol-5-yl)
thio-2-oxo-1-methylpro4xy)-3-benzamido-1-(j-diphenylmethoxycarbonyl-
Production of 1-triphenylphosphoranylidenemethyl)azetidin-2-one 1.20!1 of the product from the previous section +61 was dissolved in chloroform 40
Add mML,) liphenylphosphine 0.57I to d,
After stirring at room temperature for 15 hours, washing with saturated M backwater, MgSO4
After drying! ′〉Shrink.

The residue is purified by column chromatography on silica gel (solvent benzene-ethyl acetate (2:l)) to yield 0.86 g (53%) of Table IM compound.

IR (CHC/!3), J/ (C1n-')
: 1765. 1735. 1658°ax +619°Reference example 5 n+ (3R, 4R) -4-((+s)-3-
iodo-2-oxo-1-methylpropoxy)-3-benzamido-1-(1-diphenylmethoxycarbonyl-2-methylprop-1-eny7t, )azetidine-
2-one Reference Example 3 (!・329 of the product of item 31) was converted into acetone 3
Dissolve in 0 ml of sodium iodide 0.9! ! and stir at room temperature for 20 minutes and concentrate. Dissolve the residue in ethyl acetate and dilute with thiosulfuric acid) I
Wash with pressurized water and dry with MgSO4 CO2
1.32.9 (g6) of the title compound of CHph2 is obtained.

NMtlt(CDC, g 3 ), δppm: 1
．． 40 (3H, d, J = 6-13Hz.

-CHCH3), 2.07(3H,S,='CH3
), 2.30(3!(,s.

1cH3), 3.56.3.76(2B, ABq,
J = to)Iz.

-Cri21), 4.44 (IIl, q, J =
6.8Hz, -CHCH3).

4.83 (IIL dd, J = 7. IHz,
3-H), 5.08 (IH.

d, J = 1llz, 4H), 6. '70
(IT(,g, -CIIph2).

7.00 ~ 7-90 (15H, m, C6H5X3) (
21(3Iz, 4R) -4-((+s)
-2-oxo-1-methylpropoxy)-3-hencyamide-1-(+-diphenolmethoxycarbonyl-2
-Production of MethiAprone (0-1-enyl)azetidin-2-one 32g of the product I' from the previous section (1) was dissolved in 15ml of methylene with 1K of salt, and the bottom surface was cooled with water.3. +2g, Vinegar Q
Add 2-9 tnl and boil for 30 minutes at 4 degrees Celsius.
Rinse the furnace liquid with saturated sodium bicarbonate water and water, and add MgSO
4. Dry and concentrate.

Column chromatography of residual silica dal
-A (4:l)) to give 0.755' (70%) of the title compound of the following formula.

In (CJIC/!3), v (cta-')
: 1771.1723.1665°ax 604 N7m (CLICJ3), δppm:
l-28(3Tl, rl, J = 'IITy
,.

-CIICl(3), l-90(3T1.a,
-COCT-1,3>, 2.03(3)1. s.

=\CH3), 2.25(3H,n,HaCll3),
4.17(lIl, q, J= 7Hy,,
-CpCH3), 4.79 (IH, dd, J =
7. IIIz.

3-H), 5.0I(IIl, d, J = H
Tz, 4-)i), 6・87(In, Fl,
-CHph2), 7.00 to 740 (15H, m,
C6H5×3).

+a+ (3R, 4R) -4-((+ s
) -2-oxo-1-methylproν”? Kishi)-3
=Henduamide-1-(+-diphenylmethoxycan 1
．． ? Ni-1-hydroxymethyl)azetidine-2-
The product 210~ of the previous section (2) is coupled with methylefylzine chloride. Zinc dust 50 rT'p, ri
i - Add 0.05 mA of acid. The temperature was raised to 0°Ct, and 510q. Vinegar 0.5 rJ added R0 same? 7A r
Stir for 309'1 at rT and allow. Satisfy P liquid f1
1i after washing with sodium bicarbonate solution and then water and drying with MgSO4;
'! Shrink.

Purification of the residue by column chromatography on silica gel affords the title compound of the following formula (115-(57 width)) 0xR(CH
C/i3), pmaX(cti-'): 3450
．． 1780-1745+1724, 1663 NMR (CD Cl3) δppm: 1
．． 17. 1.3g (3T1.d, -CJICdan3)1
2.00.2-04 (3H,!!, -COCI(3)
, 4-30.4,45(II(.

q, -CiCH3), 4.61.4.70(IH,
+(d, 3H).

A, 76, 4. '? 4(IIl, d, 4-)I)
, 5, 30.5-40 (lII.

br* 8. -cdanOH), 6.88.6. qO(l
it, s, -Cpph2).

7.00~7. FO (!5H, m, C6+15×3)
.

+a (3n, 4R) -4-((+s)
-2-oxo-1-methylzoloy”? K-N-3
-Production of benzamide-1-(1-diphenylmethoxycarbonyl-1-chloromethyl)acetinon-2-one Dissolve l l of the product from the previous section (3), 5 Jn7 in methylene chloride 2 me 87 FL, pyridine 3211 under water cooling.
Add 31 μt of 1-% thionyl chloride, stir at the same temperature for 30 minutes, and then pour into ice water ◇ Yes (separate the 14 layers and wash with 1 U saturated chloride water and then with water.
-1Mg After drying with SO4 and concentrating, 1 of the title compound was obtained.
Obtained 09 hits (92 width).

NMR (Cl3<:i3), δppm:
1-26. 1.28(3)1. d, -C)I
CC84゜l, 96 (3H, s, HCH3), ”
;! , 08 (3H, Fl, ``'5CH3).

4.22.4.25 (+ear, q, -CHCH3),
4.67.4-72(l) Ldd, 3-H),
5.3+, 5.47 (IH,'d, 4-H),
6.25(IH,m, -CHCυ, 6-83.6
．． 87 (lH,"g, -C, ILph2).

7.00-740(15)1. m, CTl5x3)
.

151 (31?1.4 R') -4-! , (l S
) -2-oxo-1~methylpropoxy)-3-penzamide-+-(1-nophenylmethoxycarbonyl-1-phosphoranylidenemethyl)azetidin-2-one formation, previous'ff4 (4i) of the product 195η was dissolved in chloroform (3 meKffi), then IJ phenylphosphine 190+++7 and triethylamine 44 my were added, and the mixture was heated at room temperature for 1 hour.

Pour the reaction solution into ice water, separate the organic layer, wash with saturated sodium bicarbonate solution, then water, dry with hlg SO4, and evaporate.
Purification of the residue by column chromatography on silica gel affords the title compound 144rv (539Il).

xn(crrci3), pmaX(crn-'):
1763.1720.1660゜625 Reference Example 6 (3R24R)-4-((+s)-+ -1-ethoxycarbonylethoxy)-3-penzamide-I-(1-diphenylmethoxycarbonyl-2-methylprop-I-ene A) Production of azetidin-2-one (IR,58)-3-F227 used in Reference Example 1(1)
L-6-(1-diphenylmethoxycarbonyl-2-methylgulo7°-1-enyl)-7-oxo-4-oxa-2,6-diazabicyclo[3,2°0]hept-2-
DL-α was used in Reference Example 1.1 [11].
-Milk Pa Instead of ethyl ester, L-(+)-lactic acid ethyl ester A-35ml was dissolved, and trifluoromethanesulfone IJ 0.5. , p
.

was added, stirred at room temperature for 1.5 hours, and diluted with 200 me of sodium bicarbonate solution.
and leave it to stand for 30 minutes under water cooling. Remove the aqueous layer and pour the resulting oil into 70ml of ethyl acetate, 1VC.
Dissolve, wash with saturated saline, then water, dry over Mg5o4, and then condense.

The residue was subjected to silica gel column chromatography (11
Purification with benzene-ethyl acetate (7:l) and crystallization from ethyl ether yielded 19 compounds (n) in reference example 1(1), namely the title compound 4, 3. p (34%)
get. Bone collection was improved compared to the case of Reference Example 1 (1).

1076-

Claims (1)

[Claims] 1. General formula [wherein R+ is a hydrogen atom or a methoxyn group, R2
R represents a lower alkyl group, R3 represents a methyl group-halomethyl group or a group of the formula -CT (2-8-Hot (where TIet represents a v cylocyclic group which may have a substituent), Furthermore, A represents a hydrogen atom or a car-1?xyl protecting group], a 7β-amino-2-alkyl-1-oxa-1-dethia hepphalostyrin compound.2. RCO- represents an acyl group, R2 represents a lower alkyl group, R3 represents a methyl group, a halomethyl group or a 4
Formula-CH2S fI#1t (where lie t is Fj
The azetidinone compound of the following formula (in the formula,
RCO-* R21R31A' has the same meaning as above) is terminated, and the 7α-
The group IζCO- is removed from the amino group by a known reaction to produce a compound of the following formula (wherein R21R31A' has the same meaning as above), and this compound is reacted with an aromatic aldehyde P to produce the following formula ( In the formula, R2+ R3,A/ has the same meaning as in the previous) 1i. A compound of the Schiff salt J5 type (R4 represents an aromatic group) is produced, and the Schiff-based 7α-amino group of this compound is subjected to a known configuration inversion reaction or β-methoxylation at the 7-position. A compound of the following formula (in the formula, R+ LJ: represents a yk elementary atom or a methoxy group, and 1R31:L4+ A' has the above meaning) is produced by performing a known configuration inversion reaction, and Then, the thick base group R4-(Jl =) is cleaved from the compound using a conventional method, and the necessary carboquine retaining group (A') is further defermented.
', Y character, general formula (wherein, R1+ R2* R3V-L nll H
of 7β-amino-2-alkyl-1-oxa-1-dethyloxyalosborin compounds having %S D'FC, where A is a hydrogen atom or C' represents a Manufacturing method O