JPS5933285A - Novel carbapenem compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (X is O or S; Y is 1-methylhydroxyethylidene, etc.; Z is a H or a protecting group, e.g. an alkali, etc.; R is acetyl, etc.; the part of the dotted line is a single or double bond). EXAMPLE:p-Nitrobenzyl 3-(acetoxymethyl)-6-(R)-(2-oxo-4-methyl-1,3-dioxolan-4-yl)- 7- oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate. USE:An antimicrobial agent. PROCESS:A silyl group is removed from a compound of formula II, and phosgene is reacted with the resultant compound. The reaction product is then oxidized to give a compound of formula III, which is then reacted with a nucleophilic reagent, etc. and oxidized. The protecting group is then removed to afford a compound of formula IV. A glyoxylic acid ester, etc. is then reacted with the compound of formula IV, and the OH group is substituted by a halogen. The resultant compound is then reacted with triphenylphosphine to afford the compound of formula V, which is then heated to carry out the ring closure and give the aimed compound of formula I (Y is 2-oxo-1,3-dioxolan-4-yl).

Description

[Detailed description of the invention]

The present invention relates to the formula: [wherein, A hydrogen atom, an alkali or alkaline earth metal atom, or a protecting group for a carboxyl group, k represents an acetyl group or a heterocyclic group which may be substituted with a lower alkyl group, =
= represents a double bond when Y is a 1-methylhydroxyethylidene group; 2-, which may have an alkyl group,
When it is an oxo-1,3-dioxolan-4-yl group, it represents a single bond.] This invention relates to a novel carbapenem compound represented by the following. Research and development of carbapenem compounds has been actively carried out recently, starting with the discovery of chenamycin (see JP-A No. 51-73191).
(see No. 9), but few compounds that can be put to practical use have yet been found. The present inventors have completed the present invention by discovering that the compound represented by formula (I) is chemically stable and has excellent antibacterial activity. (R type) (S type) 2-oxo-1, which may have an alkyl represented by [wherein B is hydrogen or alkyl, especially methyl, the dotted line represents α configuration, and the thick line represents β configuration] 3-dioxolane-
It is a 4-yl group or a 1-methylhydroxyethylidene group represented by the formula: The compound of the present invention is fundamentally different from the compound disclosed in JP-A-56-122379 in that Y is a group represented by formula (IT) or formula (TIT). In formula CI), X is an oxygen atom or a sulfur atom, preferably a sulfur atom. R is an acetyl group, a heterocyclic group which may be substituted with a lower alkyl group, for example, a lower alkyl group of the formula: [wherein R1 is hydrogen or a lower alkyl group] Sometimes 1,
3.4 - Thiadiazolyl group or a tetrazolyl group which may be substituted with a lower alkyl group represented by the formula: [In the formula, kl has the same meaning as above]. Preferred R is 5-methyl-tetrazol-5-yl group, 1,3.4-thiadiazole-
2-yl group, 5-methyl-1°3.4-thiazole-2
-yl group. Z is a hydrogen atom, an alkali or alkaline earth metal atom (
(e.g., sodium, potassium, lithium, lucium, etc.) or carboxyl group protecting groups (e.g., tertiary butyl group, P-nitrobenzyl group (hereinafter abbreviated as P N B), acetoxymethyl group, pivaloyloxymethyl Group (
(hereinafter abbreviated as POM), l-ethoxycarbonyloxyethyl group, P-methoxybenzyl group (hereinafter abbreviated as C1) MR), phthalidyl group, phenyl group, indanyl group, etc.). Preferred Z is POM or sodium. The compound according to the present invention can be named as a 1-a-a-bicyclo(3,2,0]]hepter-2-en-7-onecarbapenem HM conductor represented by the formula: For example, in Example 1 below. The target compound (compound number 1:9) represented by the formula: produced is P-
Nitrobenzyl 3-(acetoxymethyl)-6-)-
(2-oxo-4-methyl-1,3-dioquinrane-4
-yl)-7-oxo-1-aza-bicyclo[3,2,
0) Hebut-2-ene-2-carboxylate. According to this nomenclature, the above compounds

Representative compounds according to the present invention other than [9] are listed below. Incidentally, after each compound name, a compound number used throughout this specification is attached. P-nitrobenzyl 3-(acetoxymethyl)-6-
(1-methylhydroxyethylidene)-7-oxo-1
-aza-bicyclo[3,2,0]but-2-ene-2
-carboxylate (compound number [10]), pivaloyloxymethyl 3-(acetoxymethyl)-6-(R
)-(2-okyne-4-methyl-1,3-dioxolan-4-yl)-7-oxo-1-aza-bicycloC3,
2,0:13 hebuc 2-ene-2-carboxylate (compound number [12)), pivaloyloxymethyl 3
-(acetoquinemethyl)-6-(1-methylhydroxyethylidene)-7-oxo-1-aza-bicyclo[3°2.0)but-2-ene-2-carboxylate (compound number CILI), 3- (acetoxymethyl)-6
-(2-oxo-4-methyl-1,3-dioxolan-4-yl)-7-oxo-1-aza-bicyclo[
3,2,0]hebut-2-ene-2-carboxylic acid (compound number [11]), pivaloyloxymethyl 3-C (
1-methyltetrazol-5-yl)-thiomethyl, 1
l-6iS)-(2-oxo-4-methyl-1,3-dioxolan-4-yl)-7-oxo-1-aza-bicyclo[3,2°0]but-2-ene-2- carboxylate (compound number C24)), pivaloyloxymethyl 3-C(1-methyltetrazol-5-yl)-thiomethyl)-6-(1-methylhydroxyethylidene)
~7-oxo-1-azabicyclo[3°2.0]but-2-ene-2-carboxylate (compound number [2
j]), pivaloyloxymethyl 3-C(1-methyltetrazol-5-yl)-thiomethyl]-6-(R
)-(2-oxo-4-methyl-1,3-dioxolan-4-yl)-7-oxo-1-aza-bicyclo[3,
2,0]hebut-2-ene-2-carboxylate (compound number [26]), pivaloyloxymethyl 3-C (
2-methyl-1,3,4-thiadiazol-5-yl)
-thiomethyl)-6-(S)-(2-oxo-4-methyl-1,3-dioxolan-4-yl)-7-oxo-
1-aza-bicyclo[3,2,0:] to but-2-ene-2-carboxylate compound number [27]), pivaloyloxymethyl 3-1:(2-methyl-1,3,
4-thiadiazol-5-yl)-thiomethyl]-6-
(1-methylhydroxyethylidene)-7-oxo-1
-aza-bicyclo[3,2゜0]but-2-ene-2
-carboxylene 1- (compound number 1'::28:))
, pivaloyloxymethyl 3-[(1,3,4-thiadiazol-2-yl)-thiomethyl)-6-(S)-
(2-oxo-4-methyl-1,3-dioxolane-4
-yl)-7-oxo-1-aza-bicyclo(3,2,
0) Hebut-2-ene-2-carboxylate (compound number C2L]), pivaloyloxymethyl 3-C (
1,3,4-thiadiazol-2-yl)-thiomethyl)-6-(1-methylhydroxyethylidene)-7-oxo-1-aza-bicycloC3,2,O,:]]hept-2-ene-2- Carboxylate compound number C30)
), P-methoxybenzyl 3-C(1,3,4-thiadiazol-2-yl)-thiomethyl)-6-(SL
(2-oxo-4-methyl-1,3-dioxolane-4
-yl)-7-oxo-1-aza-bicyclo(3,2,
Ol to but-2-en-2-carboxylate (compound number C34)), sodium 3-[(1,3,4-thiadiazol-2-yl)-thiomethyl)-6-(S)
-(2-oxo-4-methyl-1゜3-dioquinrane-
4-yl)-7-oxo-1-aza-bicyclo(3,2
, OF hebut-2-ene-2-carboxylate (compound number [35]), and sodium 3-[(1
,3,4-thiadiazol-2-yl)-thiomethyl)
-6-(1-methylhydroxyethylidene)-7-oxo-1-aza-bicyclo CI3.2. (l hepta-2-
En-2-carboxylate (Compound No. C36). Other compounds encompassed by the present invention may be named similarly to the compounds described above. The method for producing the compound of the present invention represented by formula (I) will be described in detail below. In addition, in the following description, starting materials,
Intermediates and target compounds are represented by chemical structural formulas and/or corresponding compound numbers, and as a general rule, chemical names are omitted except for compounds deemed necessary (compounds represented by general formulas are shown in Roman numerals, Individual compounds are represented by Arabic numerals). In addition, the chemical structural formula is written by simplifying the methyl group, methylene group, methine group, etc. The simplified portion has a meaning generally recognized by those skilled in the art, and representative examples thereof are illustrated below. /\,;y ,,,,,,,-,,--CJ(2C1
The compound of the present invention where l = Ct12 can be synthesized by either of the following synthetic routes 1 or 2. Synthetic route 4th step 0ff) (XIIT)↓
8th process (XV) (XVT)
In the above formula, Y may have alkyl2
-oxo-1,3-dioquinran-4-yl group, Z is a carboxyl group protecting group, φ is a phenyl group, wavy line (~-)
represents an α or β bond. A compound in which Y is a 1-methylhydroxyethylidene group and a compound in which Z is a hydrogen atom or an alkali or alkaline earth metal atom is a compound (XVI) as described below.
It can be derived from Each step will be briefly explained below. In the first step, 4-allyl-1-dimethyl-[butyl-
For example, hydroxyacetone trimethylsilyl ether (C■■3COCI■20
After reacting Si(CII3)3), the silyl group is removed to form a compound [1] [wherein a and b represent a mixture of absolute configurations of R(a) and 5(b)]. By reacting this with phosgene, 1-t-butyldimethylsilyl-, in which the amine 7 group at the 1st position is protected, is obtained.
3-(2-oxo-4-methyl-1゜3-dioxolan-4-yl)-4-allyl-azetidin-2-one [1
] (a compound represented by the general formula (Vllf)) is obtained. In the second step, the allyl group of the compound (■) is oxidized to produce an epoxy compound (■). This reaction is carried out in a halogenated hydrocarbon solvent such as methylene chloride or chloroform.
This is carried out using organic peracids such as chloroperbenzoic acid, peracetic acid, and perphthalic acid. Both reaction temperature and reaction time are not limited, but it is preferable to react at -10 to 10°C for 10 to 50 hours. The reaction mixture can be treated in a conventional manner and purified by silica gel column chromatography. This reaction yields α- and β-epoxy compounds, both of which can be used in the next third step. In the third step, the epoxy compound (IX) has the formula: I I
Reacting a nucleophile represented by X-R or a reactive derivative thereof (including converting it into a reactive derivative in the reaction system),
Hydroxy compound (X) is obtained. As the solvent, in addition to the above-mentioned halogenated hydrocarbons, ethers such as T)IF can also be used. It is preferable to react at 0° C. to room temperature for 10 to 20 hours. In the fourth step, hydroxy compound (X) is oxidized to produce ketone compound (XI). As the oxidizing agent, it is preferable to use Collins reagent or Jones reagent. Preference is given to using halogenated hydrocarbons, especially methylene chloride, or ketones, especially acetone, as solvents. The reaction takes place at 0°C to room temperature for 1 to 2 hours. The fifth step is the step of removing the protecting group for the β-lactam nitrogen atom, in this case the [-butyldimethylsilyl group]. This reaction is preferably carried out using an organic ammonium salt, such as tetraethylammonium fluoride (Et4NF), in a polar solvent such as tetrahydrofuran (T). The reaction is usually carried out at -10 to 30°C over 10 minutes to 3 hours. It should be noted that the protecting group for the β-lactam nitrogen atom is of course not limited to the [-butyldimethylsilyl group, and even if other protecting groups are used, they can be removed by conventional methods. In the sixth step, the ketone compound (■) from which the protecting group has been removed is reacted with a glyoxylic acid ester represented by the formula: 0IIC-COOZ (Z is a carboxyl protecting group) or its hydrate to produce a compound (Xllr). do. This reaction is preferably carried out in THF at 0°C to room temperature for 5 to 20 hours. In addition, when using a hydrate of glyoxylic acid ester, it is preferable to carry out the reaction in the presence of a molecular sieve. This step also involves reacting the compound (Kari) with glyoxylic acid and then applying the carboxyl protecting group Z to the resulting product.
It may be a two-step reaction in which a reactive derivative of I-1 is reacted. The seventh step is a step of replacing the hydroxyl group of compound (XIll) with a halogen. This reaction is preferably carried out using a conventional halogenating agent such as thionyl chloride and a base such as pyridine or lutidine in a suitable inert solvent such as Tl1F at a temperature of -40 DEG to 0 DEG C. The reaction time is usually 30 minutes to 1 hour. In the eighth step, the halogenated compound (xrv) nitriphenylphosphine is reacted to form a phosphorus-ylide compound (
XV) is manufactured. This reaction is carried out using triethylamine, 2,
Preferably it is carried out at about room temperature in the presence of a base such as 6-lutidine. The reaction time is usually 10 to 20 hours. The ninth step is to ring-close the ylide compound (XV) by heating it in a solvent to obtain the desired carbapenem compound (X
VI). Benzene as a solvent,
Although aromatic hydrocarbons such as toluene and xylene are preferably used, halogenated hydrocarbons and the like may also be used. The reaction is usually completed by heating at 50 to 100°C for 4 to 10 hours. Y may also have an alkyl group in the manner described below2
-oxo-1,3-dioxolan-4-yl group,
The compound cyclo[4,3,
0] -]5-nonene DI3N), 1,5-diazabicycloC5,4,0,l) -5-undecene (D13U
) etc., a compound in which Y is a 1-methylhydroxyethylidene group can be obtained.
Catalytic hydrogen reduction in the presence of carbon yields a free carboxylic acid in which Z is a hydrogen atom. Of course, from this free carboxylic acid, a compound with another carboxyl protecting group (XV
T) can also be obtained. The compound (XVI) in which Z is an alkali or alkaline earth metal atom can be produced from a free carboxylic acid by a conventional method, but the compound (X It can also be obtained by treating the reaction product with a suitable alkali or alkaline earth metal bicarbonate to make it weakly alkaline. In the latter case, a compound in which the 2-oxy-1,3-dioxolan-4-yl group, which may have an alkyl at the 6-position of the carbapenem ring, is cleaved and converted into a hydroxy, siethylidene group, which may have an alkyl, is used as a secondary compound. may occur. Synthetic Route 1 described above is particularly suitable for the synthesis of compounds in which Natsu is acetyl. This synthetic route is exemplified in Examples 1 to 6 below. Synthetic Route 2 and Fourth Step (XVI) In the formula, the meanings of Y, 7., φ and the wavy lines (8~) are the same as in Synthetic Route 1. In this synthetic route as well, the operations in each step are substantially the same as those explained in Synthetic Route 1. is the same as for synthetic route 2.
The first, second, third, fourth, fifth, sixth, seventh and eighth steps are the first, sixth, second and seventh steps of synthetic route 1, respectively.
, eighth, third, fourth and ninth steps. Naturally, the compound (XVI) obtained by this synthetic route is also a compound in which Y is a hydroxyethylidene group that may have an alkyl group as explained in Synthetic Route 1, and a compound in which Z is a hydrogen atom or an alkali or alkaline earth group. It can be converted into a compound that is a similar metal atom. Synthetic route 2 is particularly suitable for the synthesis of compounds in which 1 is a heterocycle. This synthetic route is exemplified in Examples 7 to 15 below. It shows excellent antibacterial activity against various Durham-negative bacteria and Durham-positive bacteria, and can be used for the treatment of various bacterial diseases such as purulent diseases and pneumonia.The compounds of the present invention can be administered orally (~ 1-7 days) or non-menstrual [-
It can be administered once (1-6y/day), and can also be used as an external preparation (concentration: 1-10γ). Hereinafter, the method for producing the compound of the present invention will be described in detail with reference to Examples. Example 1 Compound

Synthesis of [9] t) (1) [1) [1] 1)-1) Synthesis of compound [1'] A hexane solution of 3.2 g of diisopropylamine and 1.5N-n-butyllithium in 50 rnl of tetrahydrofuran 20- Make a lithium diisopropylamide solution from This was cooled to -78°C, and lactam CI' was added in a nitrogen stream.
] 1 (see Cherr+. Comm, 1979, p. 236) 4.505' is dissolved in 16 mt of tetrahydro 7 run and stirred for 40 minutes. This is added to hydroxyacetone, :c-tyl (Cf13COCILpS).
Add 7.5ml of i(Cfchi)3) and stir for 30 minutes. Add saline and ethyl acetate to the reaction solution, and separate the ethyl acetate layer. This is dried and concentrated. Dissolve the residue in 30 Tnl of methanol, add 3 ml of acetic acid, and leave at room temperature overnight. When the reaction solution is concentrated and the residue is purified by silica gel chromatography, the steric substance at the α-position of the 6-position side chain of the diol of formula [1'] is obtained from the fraction flowing out with a benzene-ethyl acetate (1:1) mixture. 5 isomers 3.027 and 2 isomers 1.30! yield. 1) -11) Synthesis of compound [1] Diol [1'] 5-body 3.02F was dichloromethane 2
Dissolve in a mixture of 1.60 P of 0- and pyridine, add a toluene solution of phosgene (3M, 3.6 ml) under water cooling, and stir for 30 minutes. The reaction solution is diluted with ethyl acetate, washed with water, dried, and concentrated to obtain S isomer 3.107 of compound [1]. Similarly, from 1.30 g of diol [1'], 1.54 of the R isomer of compound [1]! Get an F. [l] [2] Compound [1] 1.40 p in methylene chloride 20 ml
2.3v of m-chloroperbenzoic acid was added at 0°C, and the mixture was stirred at room temperature for 48 hours. The reaction mixture is washed twice with an aqueous sodium bisulfite solution, then washed with an aqueous sodium bicarbonate solution and brine in sequence. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with a mixture of ethyl acetate and benzene-1=2) to obtain crystals of two types of epoxy compounds [2] with different polarities. Yield a of relatively less polar isomer [2a] 5
60 meters? , relatively polar isomer C2+3]. [2a] NMR (CDC43): δ0.23
(31-TlS), 0.27 (311,S), 0.
97 (9111S), 1.60 (311,S),
1.50~3.00 (5111m), 3.33 C1
0, d, J-211z), 3.85 (lH, nl
), 4.16 (I H1d1J=311z), 477
(111, 1d, J=811Z) [2b] N N, I R(CI)Cf3): δ023
(3H1S), 0.27 (311,S), 0.97
(9 summer 1.s), 1.57 (3Hl S
), 1.50-3.00 (51'1m), 3.30
(1) (, d, J = 211z), 3.83CI1
1, n, 4.10 (III, d, , 1 = 8.II
z ), 4.73 (1■, dlJ =8117.) [2] [3) Compound [l
l2) (mixture of two isomers) 652 and acetic acid 2
09 was dissolved in 30rnl of methylene chloride, 360μ of BF3/ether was added dropwise at 0°C, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, this mixture is washed successively with water, an aqueous sodium bicarbonate solution and brine, dried over A(gsO,i), and the solvent is distilled off under reduced pressure to obtain compound [3]. Crude yield: 6.29 compounds [3] methylene chloride 100
This solution was added dropwise to a previously prepared Collins reagent (CrOa 3) and pyridine (4.8 m dissolved in methylene chloride 20 ml) at 0°C, and after stirring at this temperature for 30 minutes. Stir for a further 2 hours at room temperature. After the reaction was completed, it was filtered, and the F solution was washed with an aqueous sodium bicarbonate solution and brine, dried over MgSO4, and subjected to silica gel column chromatography (ethyl acetate:benzene = 1:1).
Separation and purification (eluting with a mixture of ) yields white crystalline compound [4]. Yield 5.38 FNMR (CDC,
/! 3): δQ, 2Q (31(,s), 0.23
(3H1S), 0.97 (9I-1,s),
1.5 3 (311,s), 2.12(
311, S), 2.87 (2+1, ■η), 3.12
(Ill, d, J=211Z), 3.97 (II
I, n, 4.06 (IIl, d, J = 81
1z), 4.60 (211,S), 3.55 (2
+1, d, J = 13Hz) I R (CIIC) 3):
18050.1760cm-' [4]
[5] Compound [4) 11 and acetic acid 2
Dissolve in 20 μffl wo-rI-IF IQμ, and
Add t4NF693m2 at 0°C and stir at room temperature for 1 hour. After the reaction was completed, 100 ml of ethyl acetate was added, washed with saturated brine, dried over MgSO4, and purified by silica gel column chromatography (eluted with a 2:1 mixture of ethyl acetate and benzene) to obtain a crystalline product. Compound [5] is obtained. Yield 573 mg NMR (CDC) 3): δ1.6 (3HlS), 2.
12 (38, S), 2.92 (211, m), 3.2
0(IIζd, J=2Hz), 3.97(III,
m), 4.00 (1) I, d, J=311z), 4
．． ．． 27 (1tt, dlJ =8I-1z), 4.
73 (2H1S), 7.12(1)f, Broad)
[5] [6] Compound [5]
350 ”?, P N B ester 1 of glyoxylic acid (1120, C1 (O, C02PNB) 3
A mixture of 54 my and E t 3N 20 p was stirred in T I-I F 10 , / in the presence of 4A molecular sieves at room temperature for 4 hours, and after the reaction was completed, TIIF was distilled off under reduced pressure. After washing with acetic acid and drying with Mg 2 SO,i, the solvent was distilled off under reduced pressure to obtain compound [6]. [6] [7) Compound [6]
452mg of THF 10n/R1: dissolved, 2.6-
5OC7217 at -20°C in the presence of lutidine 283μ
Add 7 μl dropwise, stir at this temperature for 30 minutes, and then stir at 0° C. for 30 minutes. After the reaction is complete, add 50ml of ethyl acetate.
/ is added and the mixture is washed with saturated aqueous sodium bicarbonate solution and brine before drying over λIg S 04. After filtering Mg S04, the solvent is distilled off from the r liquid to obtain compound [7]. IR (CIICj+3): 1805CII+,
1760cm ' [7] [8] Compound [73460m? and triphenylphosphine 733'''9 were dissolved in 10 ml of dioxane, and 2.6
- 242 μl of lutidine) at room temperature for 14 hours,
After the reaction is completed, the solvent is distilled off under reduced pressure. 50 mt of ethyl acetate was added to the residue, washed with water, dried over Mg SO4, and then the solvent was distilled off. The residue was chromatographed on silica gel (eluted with a 4:1 mixture of ethyl acetate and benzene).
After separation and purification, compound [8] crystals! 5 o
omg is obtained. IR (cut) 3): 1805cm, 1740
♂1 Compound [8,1500"7@dry toluene 20
ml and heated under a nitrogen atmosphere for 4 hours (oil bath temperature: 90°C), and after the reaction was completed, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate;
When separated and purified by eluting with a 1:1 mixture of benzene, the compound

Crystals of [9] are obtained. Yield: 267
~NNfR(CI)CJ3)'δ1.63(3)1
．． S), 2.07 (3H. S), 3.03 (211, dSJ=lQflz),
3.53 (111, d1J=211z), 4.17 (
111, d, J=13Hz), 4.20 (IFI, m)
, 4.63 (1n, d, J = 13) 1z), 5.
10 (2rl, d, J=6117), 5.33 (21+
, d, J=511z), 7.57 (2r-1, ld
, J =911z), 8.17 (211,d, J
Mi911z) IR (CIIC) 3): 1805cm
, 1790cm 'Example 2 Synthesis of compound [lO] [9] [10) Compound obtained in Example 1

[9] 50 ~ δ6-benzene 0
．． Dissolve in 5 ml of DBU (1 mmol/1r) at room temperature.
After about 1 minute, 5rnl of ethyl acetate was added, and after washing with a small amount of saturated saline, Mg
Dry with SO,i. After removing MgSO4, the solvent is distilled off to obtain crystals of the compound [1O]. Yield 4
1~ NMR (CDC/3): δ2.03 (30,s
), 2.07C3H1S), 2.97 (2■f, d,
J=9Hz), 4.30 (21-118), 4.75
(111, m), 5.13 (2H1d1J=611
z), 5.37 (2H, d, J = 5Hz), 7
．． 60 C2H, d, , J=911z), 8.23
(2l-11d, J = 9Hz) Example 3 Synthesis of compound [ll] Compound [9) 11 obtained in Example 1 (Fy was replaced with ethyl acetate 3
Hydrogen catalytic reduction is carried out for 2 hours in the presence of 10% Pd-C100''19 in 0 mZ. After the reaction, the catalyst is removed with P and the solvent is distilled off under reduced pressure to obtain compound [11]. This product is It can be used as a raw material for the reaction in Example 4 without purification. Example 4 Synthesis of Compound [12] Compound [11] obtained in Example 3 was dissolved in 2 m/DMF, and 47 μm of triethylamine and pine Baloyloxymethyl iodine (I CH20COt -B u ) 86
Add μI- at 0° C. and stir for 1 hour. After the reaction was completed, 20 ml of ethyl acetate was added and filtered. After washing the P solution with water, N
Dry with 4g504. After removing MgSO,i, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluted with a 1:1 mixture of ethyl acetate and benzene) to obtain crystals of compound [12]. can get. Collection 22”g NMR (CI) CI3): δ1.25 (9N, S),
1.63 (3HlS), 2.07 (311,S)
, 3.07 (2H, dSJ=IQllz), 3.5
7 (2)1. d, J = 2) - Tz), 4.1
7 (IH, m), 4.20 (1[1, d, J=811z
), 4.60 (IH1d1J=811z), 5.10
(20, dSJ=6Hz), 5.87 (211, d,
J=511z)IR((jlc)3): 1805cm
, 1790cm 'Example 5 Compound [12]
The separately synthesized compound [12] can be separately synthesized as follows using the compound [5] obtained in Example 1-5) as a starting material. 00210M CL] [14,) Compound [5) 359 mfl, H2O, (]1O-C
0211116 ml and 3N 2531r in 5 ml of dry TII F in the presence of 4A molecular sieves are stirred at room temperature for 14 hours and catalyzed after the reaction is complete. The solvent was distilled off from the P solution under reduced pressure, and the residue was dissolved in DMF2.
Dissolve in d. To this solution IClI20C: Ot
-Bu 3121' was added dropwise at 0°C, and this /7n'r
After stirring for 10 minutes at room temperature, the mixture is stirred for an additional 5 minutes at room temperature, and 20.7 g of ethyl acetate is added. This mixture was washed with 6 L of water, then dried with IgS04, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (
After separation and purification (eluting with a mixture of ethyl acetate and benzene (2:1)), crystals of compound [14] are obtained. Yield 558 m1i'N kl R(CI)Cl3):
δ1.27 (9H,S), 1.63 (311,S
), 2.17 (311,S,), 3.00 (2H,
d1J=911z), 3.37(III, d, J=2
11z), 4.13 (III, d, J = 131-
1z), 4.17 (I If, l1l), 4.60
(1[11d, J =811 z ), 4.70(
2II, S), 5.33 (I II, Broad S),
5.63 (141, S), 5.87 (2HS (11J)
=6117. ) Compound 1:14) 558"9 as 'I'
Dissolve in 10 ml of ll F, 2.6-lutidine 13
85 μm of SOC, q, is added dropwise at -20° C. in the presence of 5 μm, and the mixture is stirred at this temperature for 30 minutes and then at 0° C. for a further 30 minutes. After the reaction was completed, ethyl acetate 50- was added, washed with saturated aqueous sodium bicarbonate solution and brine, and MgS
After drying with O,i, the solvent was distilled off under reduced pressure to form the compound [
15] is made into one tatami mat. Accommodation @ 560 "If 1 1 R (CHC) 3): 1805 cm, 176
0cm2) [15,1560m? and triphenylphosphine 616 mV in dioxane 5 m
In the presence of 2.6-lutidine (203μ) dissolved in l, 1
The mixture was stirred at room temperature for 4 hours, and after the reaction was completed, the solvent was distilled off under reduced pressure. Add 50 ml of ethyl acetate to the residue, wash with water, and then dry with fg So 4. Nfg SO,i was removed by P, and the residue obtained by distilling off the solvent from the P solution was subjected to silica gel column chromatography (methyl nibenzene acetate=
After separation and purification (elution with a 2:1 mixture), crystals of compound [16] are obtained. 1 1R(CIl(δ3): 1805cm, 1740c
m06') [12] Compound [16] 451 IQ in dry toluene 20 ml
Dissolve in oil and heat under nitrogen atmosphere for 4 hours. Oil bath temperature = 9.
After the reaction is completed, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:benzene=l:1) to obtain crystals of compound [12]. Yield 1 30
"? The structure of this compound completely matched that obtained in Example 4. Example 6 Synthetic compound of compound [13]

The same procedure as in Example 2 was carried out except that compound [12] was used instead of [9] to obtain oily compound [13]. The crude yield was 15"iZQ, and this was subjected to high performance liquid chromatography (Nucleosil C18, N4eOI■-1Lp (
6/4 V/V)). Yield 2”?NMR
(CDC) 3): δ1.27 (911, S), 2.0
2 (31tS), 2.07 (3H,S), 2.98
(2111d, J=91-1z), 4.29 (2H
, S ), 4.74 (if-[, m), 5.05 (
211, (1, J=5117, ), 5.90 (21
-1, dSJ =5+1 y, ) Example 7 Compound [
24] Synthesis 1) Synthesis of Compound C171)) Compound [:I71>'14.50 y was dissolved in a mixture of 30 rnl of tetrahydrofuran and 1.6 m/l of acetic acid, and tetraethylammonium dihydrate 2 was added to the mixture. .52
Add and stir at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with brine, dried, and concentrated. Purification of the residue by silica gel chromatography gives compound C17b12.819. C17J [□8]C02P(x“Compound C
17b) 500m9 O, J: H'H20-CI (
0-Co21-1229~ is dissolved in THFIOm/,
In the presence of 4A molecular sieve, E13N494μ)
was added dropwise at 0° C., stirred at this temperature for 30 minutes, and then stirred at room temperature for 5 hours. After the reaction is completed, the mixture is filtered and the solvent is distilled off under reduced pressure. Dissolve the residue in 2 ml of DMF,
Add 590 μffl of ICHOCOt, Bu dropwise at o'c, stir at this temperature for 10 minutes, and then stir at room temperature for 5 minutes. Next, 20 ml of ethyl acetate was added, washed with water, dried over MgS04, and the solvent was distilled off under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluted with a 1:2 mixture of ethyl acetate and benzene) to obtain compound [18] as a colorless oil. Yield 743
my NMR(CI)C,,i! ): δ1.20 (
91I, s), 1.60 (3n, S), 2.5
3 (2) input [, J = 7Hz), 3.27 (ill, d,
J=21-1z), 3.83 (l r-I, 1m)
, 4.13 (III, dlJ =811z), 4
．． 40 (IH,, d, J=81-1z), 5.0
3 (I Hlm), 5.23 (2 ■■, m), 5.4
7 (11-1, S), 5.50 (11-1, S)
, 5.8° (2F-1,s) [18) [19] Compound [18
] was dissolved in 15 m/m of methylene chloride, 1.5 F of m-chloroperbenzoic acid was added at 01°C, and the mixture was stirred at room temperature for 48 hours. This mixture is washed twice with an aqueous sodium hydrogen sulfite solution, then washed with an aqueous sodium hydrogen carbonate solution and brine, and dried at λl5O4. After removing MgS04, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methyl nibenzene acetate = 2
．． :1)], the epoxy compound [Step 9] is obtained in the form of a mixture of four isomers. Bone collection 720 InL/NMR” (CD C73): δt, 23 (9L
L, s), 1.65 (3II. S), 1.5-3.0 (5 summer 1.m), 3
．． 37 (III, dl J=211z),
4.0Q (111, nl), 4.17 (111, d, ,
J = 81-1 z), 4.43 (IFI, d,
J=81-1z), 5.36 (1tl, S), 5
．． 53 (III, Broad S), 5.82 (211,
5) 81 isomers (119,1(20) Compound [19:1600 m′i to TtI F 10,,
．． 1, in the presence of 2.6-lutidine (347μ),
5oc12162μ of the mixture was added dropwise at -20°C, stirred at this temperature for 30 minutes, and then further stirred at 0°C for 30 minutes. After the reaction is complete, 50 ml of ethyl acetate is added, washed with a saturated aqueous sodium bicarbonate solution and brine, and dried with MgS04. After filtering off MgSO4, the solvent was distilled off to form the compound [20
] is obtained. Yield: 610 m9 This product can be used as a starting material for the next reaction without purification. Elemental analysis of Q: experimental value, 8.32%; calculated value, 8,17
5) Synthesis of compound [21] 610 mf of compound [20] and 791 mg of triphenylphosphine were dissolved in 10 rnl of dioxane, stirred at room temperature for 14 hours in the presence of 260 pn of 2゜6-lutidine, and after the reaction was completed under reduced pressure. The solvent is distilled off. After adding 50rnl of ethyl acetate to the residue and washing with water,
g Dry with SO, s. After removing N'lgS04, the solvent is distilled off, and the residue is separated and purified by silica gel column chromatography (eluting with a mixture of ethyl acetate and benzene=1=1) to obtain compound [21]. Yield: 690 mg IR(CHC)3): 1805an-', 1740cm
-'602POM [22] 1-Methyl-5-mercapto-tetrazole 328 m
9 was dissolved in THF5m/, and 1.6N n- was added to this solution.
265 μm of butyllithium hexane solution was added at 0°C, and 455 mg of compound [:21] was added to this mixture as TII.
Add the solution dissolved in F1m/ and stir at room temperature for 14 hours. After the reaction was completed, 5Qm of ethyl acetate was added, washed with an aqueous sodium bicarbonate solution and brine, and M g S
After drying with 04 and distilling off the solvent under reduced pressure, compound [2
2] is obtained. Rough 14009 IR (CI-IC) 3): 3500cm, 180
5C+++ 11740°-1 Compound CC2214oo'i is dissolved in 3 ml of acetone and treated with Jones reagent at 0°C. Next, methanol is added to this mixture, and the mixture is filtered, washed successively with condensed water prepared by adding ethyl acetate to the p-liquid, an aqueous sodium bicarbonate solution, and brine, and dried over MgS04. ~Ig
S04 was removed, re was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluted with a mixture of ethyl acetate and benzene = 1+1) to obtain crystals of compound [23]. 4. Yield: 320 l
! IR(CHC)3): 1805cm', 1740c
m-' [24] Dissolve 320 mg of compound [23] in 20 rnl of dry toluene and heat under nitrogen atmosphere for 4 hours. Oil bath temperature: 90
After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with a mixture of i[2 ethyl:dichloromethane-1:3) to yield compound [24] and triphenylphosphine oxy. The mixture ν(
can get. This mixture was subjected to high performance liquid chromatography (
Nucleosil C□8 reverse phase column, MeOtl:t-x
2o=7~3) When separated and purified, an oily compound [
24] is obtained. Yield 6 61119 NNHt(CI)CI3): δ1.20 (9I■, S
), 1.67 (311, S), 3.23 (211,
dlJ =811Z), 3.60 (I I-1, d
SJ=2+1Z), 3.93 (311,S), 4.
13 (tll, m), 4.20 (1■, (1, J
=8 [rz), 4.37 (I H1dSJ=f3Hz
), 4.40 (2+1, S), 5.83 (211,5)
IR(C11C)3) = 1805α, 1790 mark -
1 Example 8 Synthesis of Compound [25] 50 nIr of compound (24) was dissolved in 0.5 rnl of CD3CN, and 22 μm of DBU (1 mmol/mt toluene) was added to this solution. After the reaction is complete, ethyl acetate is added, and the mixture is washed with water and dried over MgS04. M
g S04 was removed, the solvent was distilled off from the P solution, and the residue was separated and purified by high performance liquid chromatography (Nucleosil C8 reverse phase column, MeOH: o2o = 6'4) to obtain compound [25]. It will be done. Collection II 23”
flNMR (CDCJ3): δ1.20 (911,s
), 2.00 (311, S), 3.07 (21 (
, d, J=81-17. ), 3.90 (311, S
), 4.23 (2I-1, S), 4.34 (2H1
d1J=(541z), 4.75 (1tζ +n),
5.90 (21-1S S ) Example 9 Compound [
26] Synthesis Compound [17a] can be produced from compound [17a') in the same manner as in Example 7-1). 1.33f of starting material! The yield was 0.9 (l) in the same manner as in Examples 7-2) to 7-8), except that compound C17a) was used instead of compound C171).
26]. NMR (CD C13) 'δ1.20 (91-ζS)
, 1.60 (31ζS), 3.17 (2H, d, J
=8Hz), 3.50 (II-1, dl, I=2
IIZ), 3.92 (311, S), 4.10 (III
, (11,1=8II z ), 4.40 (2)1.
s), 4.03 (III, m), 4.57 (
I It, (+, J=8Hz), 5.82 (2I-ζ
5) IR (CHCJ!3): 1805cm-', 179
0C+++-' Example io Synthesis of compound [27]
Compound [27] is obtained in exactly the same manner as in Examples 7-6) to 7-8), except that -methyl-2-mercapto-1,3,4-thiadiazole is used. NN・H((C:1)(δ3) :δ1.20 (9I
-1, S), 1.60 (311, S), 3.17 (2
1+, (11J ~ 81 [Z), 3.5oort,
dS, J=2112), 3.92(311,S), 4
．． 10 (ltlld, J=8Hz), 4.40 (2
+1SS), 4.03 (ur, m), 4.57 (I
Hlds J2811z), 5.82 (211,s
)IR(CIIC)3) :1805cm,
1790+cm' Example 11 Synthesis of compound [28] In exactly the same manner as in Example 8, compound [27] was treated with DBU in CD3CN to produce compound [28].
] and high-performance limb chromatography (Nucleosil C18 reverse phase column, N1 e 01-1 : II 2
0=6:4). NMR (CDC) 3) 2 δ1.23 (91-1,
s), 1. ．． 97 (3l11S), 2.70
(311, S ), 3.07 (211, d1J=911
z), 4.23 (21'f, S), 4.40 (2
1+, d, J=511z), 4.77 (11-1, m
), 5.90 (2+1, S) Example 12 Compound [2
Synthesis of 9] Instead of 1-methyl-5-mercapto-tetrazole, 2
The compound [2
9]. NMR (CDCJ3)'δ1.20 (91-11S
), 1.63 (3I-1, S), 3.17 (211
, [1, J=911z), 3.53 (llll, d,
J=2112), 4.10 (IIllm), 4.1
7 (I II, d, , l ~ 8 f-1z),
4.40 (111, dlJ = Btl z ), 4.
53 (211, S), 5.87 (2111s), 8
．． 90 (ltl, S)IR(CHC)3):1
805 cm-', 1790 cm-' Example 13 Synthesis of compound [30] In exactly the same manner as in Example 8, compound [29] was treated with T) RU in CD3CN to produce compound [30].
30] and high performance liquid chromatography (Nucleo'/) Lt C18 reverse layer cuff, Meoll:
1 (20-6:4) for separation and purification. NMR (CDC) 3): δ1.20 (9H1S), 1
．． 97 (311°S), 3.1o (2iζd, J=8
11z), 4.23 (21ζS), 4.50 (2H,
d, J=611z), 4.77 (If(,m),
5.90C2I(,S), 8.90(11(,S)
Example 14 Synthesis of compound [34] ■) Synthesis of compound [31] [17b] [-31] Example 7-
2), compound [17b) 1.745 fi
' in TIIF in the presence of Et3N (1,35-
Metquinhensylglyoxylate-hydrate 2.69
Compound [31] is obtained by reacting with.゛Yield 4457 NMIζ(CI)CI3): δ1.45 and 1.52
(3f-1,2x Sλ2.0~2.7 (2011
n), 3.1~3.3 (III, m), 3.5~
4.7 (311, m), 3.80 (311, S)
, 4.9-6.0 (411, m), 5.20 (
211, Broad S), 6.85(d) and 7.31
(di (4■s, J=911z, ABq) JR (CIICj!3): 3520cm', 18
10cm', 1770cm'1750cm 116
15cm' Compound [32] is obtained in the same manner as in Examples 7-3) to 7-5). Yield 3.859 NMR (cnci 3): δ3.7o Oyohi'3.80
(31(,2Xsu, 4.67 and 4.97 (21
-1,2x Broad S), 6.83 (d) 17.29
(d) (4HlJ = 9fl z, AB q )
, 7.2-7.9 (1511°m) I R (CIICz3): 1805cm-', 17
50cm-', 1620cm-'According to the method of Example 7-6), compound [32]0.917 was converted to 2-mercapto-
React with 1,3,4-thiadiazole 0.3229 (
Tll F 4 m11 using 0.5 equivalent of n-butyl lithium), hydroxyylide corresponding to compound [22] 0
．． Get 94P. This product was mixed with 172μ of DMSo,
225μ of trifluoroacetic anhydride and F, 13N
Compound [33] (1) was obtained by arsenic acid using 470 µm and post-treatment in the same manner as in Example 7-F. Yield 683IIIi+NMR (CI) CI3): δ
3.77 (311, S), 8.97 (I II. S). IR(CIrC)3): 1805cm, 1750
cm, 161f)cm-' According to the method of Example 7-8), compound [33]674''il was converted to I.ruene44
Compound [34] is obtained by heating at 80'C in m/m for 1 hour and crystallizing the product from ether. Yield 1343 rqNMR (CDC) 3): δ1.65
(3111S) 3.15 (211, d. J=91(z), 3.41 (I I-1, d1J=3
11z), 3.84 (31-(,S), 4.15 (
IHl (It, J=4 and 9■7), 4.18(d)
and 4.44(d) (211, J=91-1z, A
l1q), 4.45 (d) and 4.65(di(2
tl, J=141 (z, ABq ), 5.23 (
2tl, s), 6.89 (d) and 7.41
(dl (411, J =)3Hz, Al3q),
9.03(II-1,1s) IR(CHC)3): 1810cm, 178
Pith, 1715cm '1610cm' Example 15 Synthesized anhydrous aluminum chloride 1811''9 of compounds [35] and [36] was added to anisole 5.5
mI! and methylene chloride in a mixed solvent of 0.55 ml and cooled to -45°C. In this mixture, the compound [
34] was mixed with 5.5 ml of anisole and 0.0 ml of methylene chloride.
Add the solution dissolved in 55 ml of mixed solvent and stir. After stirring for 1.5 hours, 52
A solution of 2η1y dissolved in 22ml of water is added at once,
Furthermore, 20+++/methylene chloride was added, and the mixture was heated to room temperature while stirring vigorously. After allowing and removing the formed aluminum hydroxide, the methylene chloride layer is separated and the aqueous layer is washed twice with methylene chloride. The aqueous layer is I-I P-
20 column and elute with water. When developed with 300 rnl of water and then with 5% methanol, compound [36]
50 m/fraction containing as main component, then compound [
35] is obtained as a main component. When each fraction is concentrated under reduced pressure and then lyophilized, compounds [35] and [36] are obtained, respectively. Yield of compound [35] 59 Tu9, compound [36]
] Yield: 247 ku. NMR of compound [35] (1')20, DSS standard);
δ1.66 (311, S), 3.08 (211, d
, J ml QHz), 3.82 (1r■,d,
J=211z), 4-4.3 m C11-1, m
), 4.23 (2rt. d, J=14 old), 4.42 (dl and 4.54
(d) (211, J =711z, Al5q), 9.
44 (I H,s) JR (KBr
): 3420cm 'C broad), 1805cm
', 1795cm-', 1760cm-' Compound (3
6) NMR (D20): δ2. ．． 39 (311,s
), 3°40 (2+1, broad, J=lQHz),
4.63 (211, S), 4.79 (211, (1, J
=811z), 4.9 (I Hlm), 9.84C1
1ζS) Example 16 Synthesis of compound [45], zu/, J [38]
Compound (3D (Patent Application Shoma-627 filed by the applicant)
No. 84 (filed on April 24, 1956)) 3!2 was dissolved in 25 m/m of methylene chloride, and 0.90 y of sodium bicarbonate was added.
and 2.0 parts of m-chloroperbenzoic acid were added, and the mixture was allowed to react overnight at room temperature. 3 g of epoxide compound (38) obtained by treating the reaction mixture in a conventional manner was treated with T LI F 24
ml and add 70% tetraethylammonium to this.
Add 1.96 fI of lido and 0.61 ml of acetic acid and stir at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure, and the residue is subjected to silica gel chromatography (niacetonitrile /8 eluent) to obtain compound [39]. Yield 1.9fi' compound [38] of 1it (CI-IC
)3): 1815.1740°-1 NMR (CDC, 63): δ0.23 (3H1S)
, 0.28 (31ζ5), 0.97 (9H,S)-
All others are polygons and 11ζ of the noncompound [39]
CJ-IC) 3): 3400.1815.1765cm
'NMR (CI) (1), ): Totally multiplet and unattributable. In addition, if the isomer of compound [37] is used as a raw material,
Iζ isomers of compounds C38] and [39] are obtained. IR of compound [38) (K form) (CI-IC13):
1810.1740cm' NMII (CI') CI3): δ0.25 (3II
, s ), 0.28 (3HlS), 0197 (91
1, s), and all others are multiplex lines with no attribution. I R ((JIC) of compound [39) c, Iζ form)
3): 3400°181O11765 mark-1 NMR (CI) CI, ): Totally multiplet and unattributable. [39] [40] C02P ~ (B C02PMn c 4□) Compound [39] 1.911DTII F 34-To the solution, 2.24 P-methoxybenzylglyoxalate and 0.4 ml of triethylamine were added, and the mixture was heated at room temperature. React overnight. Concentrate the reaction solution under reduced pressure, dissolve the resulting oil in 200 rnl of ethyl acetate, and add hydrogen sulfite.)
Wash twice with IJum aqueous solution, remove water, wash with saturated saline, and dry with magnesium sulfate. Then, ethyl acetate is distilled off under reduced pressure to obtain compound [40] as an oily substance. IR (CIIC) 3): 3500 (Broad), 18
15.1765.1750 (shoulder), 1610 country-1 NMR (CDC) 3): δ3.79 (311,s)
, 6.8-7.0 (211, m), 7.2-7.4 (
211, m). Others are multiple lines and cannot be attributed. 19 ml of the compound [40] obtained above was dissolved in T' II F, cooled to -50 to -55°C, and 2,6-lutidine 2
．． 8 m/ and 1.05 m/ of thionyl chloride are added. After 15 minutes, the reaction mixture was treated according to conventional methods, and the resulting oil was dissolved in 19 ml of Ttl F and 2.6-
Lutidine 2.6rnl Totriphenylphosphine 2.5
29'E- and react overnight. The reaction product is purified by silica gel chromatography (eluent: ethyl acetate) to obtain ylide compound [41]. Yield ttt3.23g-11ζ(CI-IC)3):1810,1790 (shoulder)
, 1745.1610an-' NMR (CI) CI23): δ3.72 and 3.7
9 (31+, 5X2)%6.8~7.0 (211,
m), 7.2-7.9 (17II, m). Others cannot be attributed. Lυ21'M15 002PM8 [43] Add n-butyllithium-hexane solution (1
, 6M) was added dropwise and stirred for 10 minutes at room temperature. This solution was mixed with compound (4) 1.3P]”npg
Add to solution d and leave at room temperature overnight. The reaction mixture is concentrated under reduced pressure, extracted with ethyl acetate, and treated in a conventional manner to obtain 1.452 of the crude product of compound [5]. IR (CI-1c) 3): 3350 (broad), 18
10° 1790 (shoulder), 1750.1610σ-1 dimethyl sulfoxide 0.43 rnl methylene chloride 5.
5 ml of the solution was cooled to -70°C, and 0.57 m/ml of anhydrous acetic acid was added dropwise thereto, followed by stirring for 20 minutes. To this solution, methylene chloride 8 of the compound [5] obtained in -1x was added.
．． 5 ml solution was added dropwise and after stirring for 1 hour, triethylamine 1.2. Add n/ and stir for an additional 20 minutes. The crude product obtained by treating this reaction mixture in a conventional manner is purified by silica gel chromatography (eluent: ethyl acetate/acetonitrile (1/1)) to obtain compound [6]. (CIICi3): 1810, 1790 (shoulder), 1
750.1720 (shoulder), 1630 (shoulder), 1610,
1570 cm-' [44] Ylide compound [44] 0.8P was heated at 70°C for 1.5 hours in a mixture of 50 ml of toluene and methylene chloride, and the solvent was distilled off under reduced pressure to obtain the desired carbapenem. A mixture of compound [45] and triphenylphosphine oxide is obtained. A portion of this is purified by silica gel chromatography (eluent: benzene/methylene chloride/ethyl acetate/acetonitrile (1/1/1/2)) to obtain a pure compound [45]. IR(CIIC)3):1820.1785.1720
cm 'NMR (CI) CI3): δ3.17 (21
ζd, 9flz), 3.54 (IH, dd, 3 and 8
Hz), 3.80 (31ζS), 3.92 (311,s
), 418 (III, 't d, 3 and 9l-
1z), 4.35-4.75 (41-T, m), 4.
98 (1tl, [, f31-1 z ), 5.19 (
21ζS), 6.88d +7.35d (ABq, 91
1z). UV(EtOl 2 λmax 228, 24
6, 273, 280 nm If the R isomer of compound [44] is used as a starting material, the isomer of compound [45] can be obtained. K-body I (C11C) 3): 1815.1785.1
715Cm' NMR (CDC) 3): δ3.11 (214, d, 9
l-1z), 3.63 (1 summer 1.t, 311z
), 3.78 C3H,S ), 3.88 (3
111S), 4.19 (Ill, td, 3 and 8H
z), 4.4-4.6 (4Il. m), 5.01 (III, t d14 and 811
z), 5.18 (2IζS), 6.86d +7.34
d (ABq, 41-1, 911z). Synthesis of Compounds [46] and [47] A solution of 230 m9 of the crude product (containing triphenylphoschin) of Compound [45] in a mixture of 3 ml of anisole and 0.3 ml of methylene chloride. , aluminum chloride 160 mi? is added to a solution of 3 ml of anisole and 0.3 ml of methylene chloride at -55°C and stirred for 35 minutes. Add 1 liter of bicarbonate to this reaction mixture.
-IJum 454m9 and phosphate buffer (pH 7,0) 12
7-? u
Let r. After filtering the reaction mixture to remove insoluble matter, the methylene chloride layer was separated, and the aqueous layer was diluted with methylene chloride.
Wash twice. The aqueous layer is loaded onto a column of IIP-20 and eluted with water. After the inorganic substances are eluted, the compound [47
] is obtained as a main component, and then 14 rnl of a fraction is obtained as a main component of compound [46]. Lyophilization of each fraction yields 5 mg of compound C47) and compound (46) 8 nr9. UV (T-120) of compound [46]: 238 nm (
shoulder), 275 nm (ε~5,100) Uv of compound [47] (1■20) = 226 nm, ~2
66m R isomer of compound [45] 228 mW (crude product)
When using as a starting material, the summer (isomer 14m7 of compound [46] is raised by 1. Compound C46) CR form) (hal(Fr2O)'22Q
nm (shoulder), 276 nm (ε~5,700) Patent amount 1
Head person Shionogi Pharmaceutical Co., Ltd. agent Patent attorney Aoyama Aoyama and 1 other person 82

Claims (1)

[Claims] [In the formula, X is an oxygen atom or a sulfur atom, Y is a 1-methylhydroxyethylidene group or a 2-oxo-1,3-dioxolan-4-yl group which may have an alkyl group,
Z represents a hydrogen atom, an alkali or alkaline earth metal atom, or a carboxyl group protecting group; I (represents an acetyl group or a heterocyclic group which may be substituted with a lower alkyl group; When Y is a methylhydroxyethylidene group, it represents a double bond; when Y is a 2-oxo-1,3-dioquinran-4-yl group, which may have an alkyl group, it represents a single bond] .