JPS5936677A - Carbapenem compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [X is O, or S; Y is H, or OH which may be protected; Z is H, alkali metal atom, or carboxy-protecting group; R is 4-pyridyl, or heterocyclic group shown by the formula II, or formula III(R<1> is H, or lower alkyl), etc.]. EXAMPLE:Pivaloyloxymethyl 3-[( 1-methyltetrazol-5-yl )-thiomethyl]-6-ethyl-7-oxo- 1-aza-bicyclo[3.2.0]hepta-2-ene-carboxylate. USE:An antibacterial agent. Showing antibacterial activity against Gram-negative and Gram-positive bacteria other than Pseudomonas. PROCESS:A compound shown by the formula IV is alkylated at the 3-position, reacted with a glyoxlylic ester to give a compound shown by the formula V, the allyl group is epoxidized, the OH group is halogenated, the halogenated compound is reacted with triphenylphosphine to give a compound shown by the formula VI. Thiscompound is reacted with a compound shown by the formula HX-R to give a compound shown by the formula VII, the OH group is oxidized, and the prepared compound is heated, to give a compound shown by the formula I .

Description

[Detailed description of the invention]

[In the formula, X is an oxygen atom or a sulfur atom, ■ is a hydrogen atom or a hydroxyl J which may be protected,
k may be substituted with a heterocyclic group, especially a 4-pyridyl group or a lower alkyl group; 3. Representing a 4-thiadiazolyl group or a tetrazolyl group] A new carbapenem compound (related to penem compounds) has recently been actively researched and developed, starting with the discovery of chenamycin (see JP-A-51-73191). (For example, Japanese Patent Application Laid-Open No. 56-12237
(see No. 9), but few compounds that can be put to practical use have yet been found. The present inventor has completed the invention by discovering that the compound represented by the formula (I) is chemically stable and has excellent antibacterial activity. According to formula (1), Y is a hydrogen atom or a hydroxyl which may be protected with, for example, a trialgylsilyl group.
1 (where X is an oxygen atom or a sulfur atom, preferably a sulfur atom.
k is hydrogen or a lower argyl group] Lower argyl J represented by (may be substituted with 1,3,4-thiadiazolyl group or formula = 1 ] It is a tetrazolyl group which may be substituted with a lower alkyl jA represented by [3] Preferable k is a 4-pyridyl group, a 5-methyl-tetrazol-5-yl group, or a 1.3.4- Thiadiazole-2
-yl group, 5-methyl-1,3,4-thiazole-2-
It is an yl group. The uninvented compound is fundamentally different from the compound disclosed in JP-A-56-122379 in that k is a heterocycle as described above. Z is a hydrogen atom, an alkali metal atom (e.g. sodium,
potassium, lithium, etc.) or protecting groups for carboxyl groups (for example, pivaloyloxymethyl group (hereinafter abbreviated as POM), p-nitrobenzyl group (hereinafter C, abbreviated as PNB), P-
methoxybenzyl group (hereinafter abbreviated as PMB), etc. Preferred Z is POM or sodium. The compound according to the invention is a compound represented by the formula: 1-aza-bicycloC3,2,0':]
but-2-en-7-onecarbapenem) derivative (4). For example, Example 1 described below
1] Compound (compound number 11-71) produced by the formula: Piparoyloxymethyl 3-C (2-methyl-1,
3,4-thiadiazol-5-yl)-thiomethyl]-
6-Nity-7-oxo-1-aza-bicycloC3,
2,0') hebut-2-ene-2-carboxylate. According to this nomenclature, the "-compound [7a
] Representative compounds according to the present invention other than the following are listed below. In addition, after each compound name, the compound number used throughout this specification was asked. Piparoyloxymethyl 3-(:(1-methyltetrazol-5-yl)-thiomethyl]-6-nityl-7-
Ogiso 1-aza-bicyclo [3.2.0] to buta-2
-ene-2-carboxylate C compound number [7b)
), Piparoyloxymethyl 3-C (4-pyridyl)
-thiomethyl]-6-nityl-7-oxo-1-aza-
Bicyclo[3,2,0]hebut-2-ene-2-carboxylate (compound number [7c], piparoyloxymethyl 3-C(2-methyl-L 3.4-thiadiazol-5-yl)- thiomethyl]-6-(l-hydroxyethyl)-7-oxo-1-aza-bicycloC3,2
,0) hebut-2-ene-2-carboxylate (compound number Ct2a]), pivaloyloxymethyl
3-C(1,3,4-thiadiazol-5-yl)-thiomethyl)-6-(1-hydroxy)ethyl-7-oxo-]-azabicycloC3,2,F)hept-2-ene-2 -carboxylate C compound number [12b]),
Piparoyloxymethyl 3-[(1-methyl-tetrazol-5-yl)-thiomethyl]-6-C(1-t-
butyldimethylsilyloxy)ethyl]-7-oxo-1-azabicyclo[3゜2.0]buta-2-carboxylate (compound number C1,2') + P-meI.
Quinbenzyl 3-[(1,3,4-thiadiazole-
2-yl)-thiomethyl']-6-(1-hydroxy)
Ethyl-7-oxo-1-azabicyclo r3.2.0
':]hept-2-en-2-carboxylate (compound number [14)), and
- (1-hydroxy)ethyl-7-oxo-1-aza-bicyclo[73,2,0]but-2-ene-2-carboxylate (compound number C15). 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 (■) 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 portions are generally recognized by those skilled in the art, and representative examples thereof are illustrated below. 7'\ノ2 ・・・・・ −CH2CH=CH
2 The compound of the present invention can be synthesized by the following synthetic route. Y Y (■)
αD(IX
) CX) (XIT)
(XI) (T) In the above formula, V is hydrogen, 2 is a carboxyl group protecting group, φ is a phenyl group, the wavy line represents an α or β bond, and Yl is a substituent at the 6-position of the starting material. represents. A compound in which Z is a hydrogen atom or an alkali metal atom can be derived from compound (XII) as described below. Compounds in which Y is a hydroxyl group, which may be protected, can also be produced essentially by the above synthetic route, which will be described later. Each step will be briefly explained below. In the first step, the NH of the β-lactam is protected with, for example, a tert-butyldimethylsilyl group, treated with a strong base such as lithium diisopropylamine, and then alkylated by the action of iodoethyl. By removing by a conventional method, 3-ethyl-4-allyl-azetidin-2-one (■■) is obtained. In the second step, compound (VI) is given the formula: OHC,C00
A compound (
■Produce 1i). This reaction is preferably carried out in THF at 0°C to room temperature for 5 to 20 hours. In the first reaction 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 compound C1) with glyoxylic acid, and then using the resulting product with carboxyl protection J,
(It may be a two-step reaction in which reactive derivatives of 7 and 11 are reacted. In the third step, the allyl group of the compound ('VTI'r) is oxidized to produce an evogish compound (Vllll). This reaction The reaction is carried out using an organic peracid such as tn-chloroperbenzoic acid, peracetic acid, or perphthalic acid in a halogenated hydrocarbon solvent such as methylene chloride or chloroform.The reaction temperature, reaction time, etc. are not limited. No, but +-
It is preferable to react at 1+1 to 1()°C for 10 to 50 hours. This reaction yields rt and β-epoxy compounds 11), both of which can be used in the next fourth step. The 42nd step is a step of substituting the hydroxyl group of the compound (Vlll) with halogen (11). This reaction is carried out using a conventional halogenating agent, such as thionyl chloride, and a suitable base, such as pyridine, 2,4-lutidine, etc., in a suitable inert solvent such as Tl1F at a temperature of -40 to 0°C. is preferred. A reaction time of 30 minutes to 1 hour is usually sufficient. In the fifth step, the halogenated compound (IX) is reacted with triphenylphosphine to form a phosphorus-ylide compound (X
) is manufactured. This reaction is preferably carried out in an ethereal solvent such as THF or dioxane in the presence of a base such as triethylamine or 2,6-lutidine at about room temperature. The reaction time is usually 10 to 20 hours. In the sixth step, the compound (X'J) is reacted with a nucleophile represented by the formula: I (X-R or a reactive derivative thereof (including making it into a reactive derivative in the reaction system), and (X■) is obtained. As the solvent, in addition to the above-mentioned halogenated hydrocarbons, ethers such as THF can also be used. The reaction is preferably carried out at 0° C. to room temperature for 1 to 20 hours. C19) 7 21: In A', the hydroxy compound (X■) is oxidized to produce a ketone compound (Xil).As the oxidizing agent, it is preferable to use Collins reagent or Jones reagent.As the solvent, halogenated hydrocarbon, 4 .1.,
It is preferable to use methylene chloride or ketones, especially acetone (7).The reaction is carried out at (1°C to room temperature),
One to two hours is sufficient for the reaction. The 8th-[: culm] is a step of ring-closing the ylide compound (x■) by heating it in a solvent to produce the desired carbapenem compound Il/)1 (]-). As a solvent, it is preferable to use aromatic hydrogenated hydrogen compounds such as benzene, toluene, and cylene, but halogenated 1-panhydrogens and the like may also be used. tt-iru. Usually 50-100℃
The reaction is completed by heating between 2 and 101 Rf. A compound (■) in which Y is hydrogen and Z is a carboxyl protecting group is obtained by the following two-part method, but if this compound is subjected to catalytic hydrogen ring removal in the presence of palladium/prosium, for example, A free carboxylic acid in which Z is a hydrogen atom is 1 (1). Of course, a compound (■) with another carboxyl protecting group can also be obtained from this free carboxylic acid. A compound (■) in which Z is an alkali metal ) can be prepared from free carboxylic acid by a conventional method. Compound (■) in which Z is a protecting group for the carboxyl group is treated with aluminum chloride, and the resulting reaction product is treated with an appropriate compound. It can also be obtained by adding bicarbonate of an alkali metal to make it weakly alkaline. A compound of formula (■) in which Y is a hydroxyl group which may be protected can be produced as follows. That is, by producing a compound of the formula (■■) in which ■ is a protected hydroxyl group and carrying out the reactions in the second to eighth steps using this as a starting material, a compound (■■) in which Y is a protected hydroxyl group is produced.
) is obtained. On the other hand, using a compound of formula (■■) in which Y is a protected hydroxyl group as a starting material, the reactions described in the above 2nd to 72nd steps are carried out to form a compound of formula (XII) in which Y is a protected hydroxyl group. By obtaining a compound, removing the protecting group for the hydroxyl group, and then performing the reaction in the 8th step, a compound (■) in which Y is a hydroxyl group can be obtained.Y is a hydroxyl group that may be protected, It should be readily understood by those skilled in the art that compounds of formula (1) in which 2 is hydrogen or an alkali metal can also be prepared based on one or more of the descriptions. Excellent antibacterial effect against various Durham-negative bacteria and Durham-positive bacteria except for
It can be used to treat various bacterial diseases such as purulent diseases and pneumonia. The compounds of the present invention can be administered orally (1-1 C-19/day) or parenterally at 4-6 Q/Ii),
Furthermore, it can also be used as an external preparation (fm + - (1: 1 to] 0γ). The method for producing the compound of the present invention will be described in detail below with reference to Examples. Examples: Synthesis of Compound [7a] 1) Synthesis of compound [1] (15) Compound [1] can be produced by the method of J, H, Bateson et al. (J, C, S, Ch
em, Com+u1980.1084-1085)
. Compound C1] 1.909 was dissolved in 55 ml of THF, and 1.329 g of glyoxalic acid and 13 g of molecular sieves were added. To this mixture was added 2.85 g of triethylamine under water cooling, the mixture was stirred for 10 minutes, and then left overnight at room temperature. The reaction mixture is filtered and the r liquid is concentrated under reduced pressure. Add and dissolve 8 ml of r) M F to the residue, and add 4.5 ml of bivaloyloxymethyl iodide under water cooling.
was added and reacted for 20 minutes, and then ethyl acetate (C16) IO (1 ml) was added. The mixture was washed with water and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography C eluent: ethyl acetate/Hensen- 171
) Compound [2] is obtained. The yield is 113g N M RI C1) C1+N : δ0.9B (:
NI, t, J-71-1z), 1.22 (911
-s), 1,5-2.1 (2H, m), 2.2-213
(211, m), 2.8 (I Hlm)-8,
4-8.8 (I II, m), 4.2 (I H
, pu o -1' s (011)), 4.9-6.
1 ('3)-I-m), 5°37 and 5.47 (Il
l, 2xs, 2 types of isomers 11$011), 5.8~
6.0 ([11,m)[R(CIICla):175
5bi, 1705α-1 [2]
[3] Compound [2) 8.11i1 is dissolved in 55 ml of methylene chloride, 5.8 g of 1η-chloroperbenzoic acid is added to this solution, and the mixture is left overnight at room temperature. The mixture is washed with a reconstituted aqueous sodium hydrogen oxide solution diluted with ethyl acetate, then with an aqueous sodium thiosulfate solution, and concentrated under reduced pressure. The residue is treated in the same manner as in 2) above to obtain compound [3]. Yield 3.5g NMR (CDC/a): δ1.03
(3H, L, J-7Hz), 1.23 (9H-s),
1.5-13 (8H1m), 3.5-8.9 (I
H,m)-5,23 and 557iH12XS, (two isomers H"-'v-OH), 5.76(d) and 6.
09 Cd) (2H-J = 5Hz, ABq) IR(CHCls) = 1740m, 1705CIn
4) Synthesis of compound [4] [3] [31] Dissolve 8.5 g of compound C3 in 20 liters of THF.
Cool to 0°C, add 2.2 vxl of 2,6-lutidine and 1.0 ml of thionyl chloride, and stir for 1 hour. The reaction mixture was diluted with 1,501 ml of ethyl monoacetate, washed twice with water, and concentrated under reduced pressure. The residue was treated in the same manner as in 2) to obtain compound [31]. Yield g (3') [4] 4 g of compound [4] was dissolved in ``I'11 FIQIl, 5 g of triphenylphosphine 4 and 2.6-lutidine 2.
2 Add wrl and leave in room d1,1 overnight. The reaction mixture is extracted with ethyl acetate and the extract is concentrated. Compound [4] is obtained by treating the residue in the same manner as in 2). Revenge 18. (+99 HMR(CI)CI!o): δ1.07 and 1.23
(9H+2Xs(L-ISu)'+, 5.4-5.9(
2H,m(-CO2-C112-1)-7,2-7.9
(I FI Il-m). Other unattributable peak IR (CIIC/81: 1740/?#I, 1
63(lfi'C19) [4] [5] 5-methyl-2
-Mercapto-1,3,4-thiadiazole 212■ was dissolved in 2.4 ml of THF, and n-
0.25 ml (0.4 equivalent) of butyllithium hexane solution is added dropwise and left at room temperature for 720 minutes. In this solution,
A solution of compound [4': 1470 resistant] dissolved in 2.4 m/THF is added, and the mixture is left at room temperature for several hours. The reaction mixture is concentrated under reduced pressure and the residue is treated in the same manner as in 2) to obtain crude compound [5]. Yield 564 ~ [5] C90) CO2POM [6] Sum 1Ilj! (7) Compound [5] 564wIg to 7-b
Dissolve 9ml in 1K and treat with Jones reagent at 11C. Methanol is added to the reaction mixture and filtered, and ethyl chloride is added to the filtrate, which is then washed with water, dried, and concentrated under reduced pressure. The residue is treated in the same manner as in 2) to obtain compound [6]. Collectionfft337Q'N M R(CI)C/
B): δ1.07 and 1.23 (9H12×S, (L
-Bu)), 2.68 (311,s), 4°28(
211, Broad 81, 5.27 and 5.67C2I
112×Broad S, (-CO2CI-12-1, 7,
3 [7a] Compound (6] 180w1) in 13 g of toluene at 80°C
After heating for 3.5 hours, the reaction mixture is concentrated under reduced pressure. The residue is treated in the same manner as in 2) to obtain compound [7a]. Yield 93 mg NMR (CDC1B); δ1.02 (3H1

[, J-7
Hzl, 1.22 (9H-s), 1.6-2.1
(2H, m), 2.72 (38, s), 8.0~8
．． 3 (IH-m), 8.06 (2H, Broad, J
= 9 Hz), 8.88 (IH, cd-J = 3 and 9 Hz), 4,33 (d) and 4.62 (d) (
2H, J = 14 Hz, ABq), 5.82 (d
) and 5.93 (d) (2H, J=5 Hz= A
Bq) IR(CIIC7?81:l780(In
−1755GI 'LJV(λ(ccNl
: 2 R3nm Example 2 Compound r 713 )
Synthesis of Compound C71) was prepared in the same manner as in Examples -6) to 81, except that 1-methyl-5-mercapto-tetrazole was used instead of 5-methyl-2-mercapto-1,3,4-thiadiazole. obtain. NMR (CI) C/8): δ1.03 (311,t,
J-711z), 1.23 (911, S), 1.5-1
．． 9 (21-(+ m)+3.tl-8,3(I
II, +n)+3.09 (2H,)o F, ,
l ~9117.1. 37~4.0 (' I H
lm), 8.93 (3 1, s 1, 4.46
(21-1, Broad, J = 311z), 5.9
0 (211, broad, 3 Hz) IR (cIIcl
! g):17801? I#, 17500+1 '1
Example 3 Synthesis of compound [7C] Examples 1-6) to 8 except that 4-mercaptopyridine was used instead of 5-methyl-2-mercapto-1,3,4-thiadiazole ) to obtain compound [7C]. NMR (CDC1g): δ1.02 (3H-t, J=
7Hz), 1.22 (9H1s) 1.6-2. Q (
2H1m), 2.9-8.2 (LH,m), 2.9
9 (2B, broad, J=9Hz), 8.88 (
IH-dt, J=3 and 9Hz), 4.25 (2H
, Broad, J-7Hz), 5.82(d) and 5.
93 (d) (2H, J=5 Hz-ABq), 7.
18 (2H, Broad, J-6H2), 8.43r2H
, Broad, J = 5 Hz) IR (CHC18):
1780c1+1. 1750z 'Example 4
Synthesis of Compound Cl2a] Ca]CI)''] C8) 1)-1 Synthesis of Compound [1]] Compound [a) 0.94f produced by the method described in Reference 1, e.g. ,

[-Butyldimethylsilyl chloride 0.60g, imidazole 0
．． 55f was dissolved in D M F 1 (l vrl) and reacted at 55°C for 5 hours. The reaction solution was diluted with ethyl acetate, washed with brine, dried, and concentrated. The residue was subjected to silica gel chromatography. The compound [
b] is obtained. [24) 1 1 R (CHC1!8): 1 7 30C1nN
MR (CDC/8): δ 0.07 (6x1.s) - Q. 23 (6H1s) - 0,90 (9H,s), 0.97
(9H, s), 1.18 (3H-d, 5Hz),
1.8-2.7 (2H=n+)-2,80(IH
, dd, 5 oyobi 2H2), 8.4-8.8 (I
H, m)-4,12 (IH, quint, 5 Hz),
4.9-6.1 (3B, m)1)-'ii) Synthesis of compound [8] 1.35 g of compound Cb) was mixed with 0.5 ml of acetic acid and THF.
18 resistant mixed solution, add 0.6 gM of tetraethylammonium fluoride dihydrate, and dissolve at room temperature.
Time reacts. After the reaction is completed, most of the solvent is distilled off, the residue is dissolved in dichloromethane, washed with saturated brine, dried, and the solvent is distilled off. The residue was purified by silica gel chromatography to obtain 0.90 g of compound [8]. IRrcHclg)=3400.1750α-1HMR
(CDCIV+N: δ0.05 (6H-s 1.0
．． 87 (91 (, s), 1.20 (3H, d, 5
Hz), 2.36 (2H, broad [, 5 Hz)
, 2.75 (I H-dd, 6 and 211z (, a
, (i 7 (I II, [(1,6 and 2■1),
4.15 (III, quinL, [311z
)-4,9~fi,1(311,...) O2POM 1-8 ) (9') Compound [8] 0,9 f in the same manner as in Examples 1-2) to 5)
i! 'From compound r! 11.40g is 7 yen). Yield 55% NMR (CDCIs): δ080 and 0.83
(9H12×S), 1.03 and 1.22 (911,
2×S), 5.35 and 5.75(211,2×S(
broad)), 7.2~8.0 (15tl, m), other imputed discord beak IR, (CIIClsl: + 74 (lo+
, 163oan'r 97) [9] []]0]5-Methyl-2-mercapto1.3.4-ChiyGysol2121IIgoJT11F solution 2.4 vr
l of n-butyllithium hexane solution under ice cooling.
ml (0,4 eq.) dropwise and allowed to stand for IO min at room temperature.
After i'i, compound [9] was added to this solution and 12
After reacting for a period of time, post-treatment according to Example 1-6) yields a hydroxyl intermediate corresponding to compound [5]. Crude yield: 591 g DMsol 20 μl methylene chloride solution 2.2111
was cooled to -78°C, and 145% of trichloroacetic anhydride was added to it.
Add μt and stir at this temperature for 30 minutes. Add 2 of the methylene chloride solution of the above hydroxyl intermediate to this solution.
．． Add 2 ml dropwise. After reacting at this temperature for 30 minutes, 310 μl of triethylamine was added and molded with 9Q1 for 10 minutes. Bring the anti-LIS mixture to room temperature,
'71: Extraction with ethyl acid [7, When the solvent is distilled off from the extract, compound C111:) is obtained? i) be received. Yield: 1t47.
818gNMR(CI)Cla):δ(1,051
611+s), 1゜10o, 1゛hi1.27+911
．． 2×S), 2.75 (3H+8)%5.35 and 5.77(2■1.2×S(J-do)), other unattributable peaks ((CIIC/a): 1745an , 1640
z ' [11] Compound r 1 (+ ') I Fl 71#g dissolved in acetonitrile 4.4 resistant solution with 0.1 NllC
l! Add 64.4 ml and stir at room temperature for 24 hours. The reaction mixture is made weakly alkaline by adding an aqueous solution of sodium hydrogen acetate, and extracted with ethyl acetate. Compound [1] is obtained by subjecting the extract to silica gel chromatography. Yield】】2η (yield 64%) NMR (CDCts): δ1.07 and 1.23C9
H12×S), 2.70 (3T(,s), 5.3
5 and 5.70 (2H12xs (broad)) -7
, 4-8°0 (] 5H, m), other unattributable peaks IRrCHC1aM3500m (broad),
1 1745α, 1640 Bei-1 CO2POM O2POM [12a] Compound 1 [11J84)〃g to 5.7ml of toluene! Heat for 4 hours at -80℃! (L, then toluene is distilled off under reduced pressure. The residue is subjected to silica gel chromatography for 4J to recover 20 mg of compound 1: 11) and to obtain compound r l 2 a :J. Revenue! Ti: 17 l? 1gN M R (CI) (:js
): δ1.22 (11, S), ■. 3Q (311, d, l = 3117. ), 2.72
(3H-sl, 8.0-8.3 (III, m)
, 310 C2H, d()゛Load 1-J-1(l12
), 4.0-4.4 (2H, m), 4.35rtl
) and 4.62 (d'l (2H-J= 1411
Z, Al5(+), 5. RO(d) and 5.9
3((+)(2H1J = 611z, Al5q)
IR(CIICe a) = 3600-33QQ
c'in. Synthesis of 1775 (M, 175QCn+ 'Example 5 Compound C12+)) Compound C12bl was prepared in the same manner as in Examples 4-3) to 5), except that 2-mercapto-1,3°4-thiadiazole was used instead of adiazole. get. NMR (cDcI!8): δ1.23 C9H-s)
, 132 (3H, d, J=5Hz), 8.0-8.3
(IHlm), 3.13 (2H1d (broad), J=10Hz), 4.0-4.5 (2H-
m), 4.43 (dl), 4.71 (d) (2
H,J=13Hz-ABq), 5°82cd) and 5.95(d)(2HlJ-6I(z,ABq) I R(CHClg): 3600-3300tm
, 1780n, 1750cm' 5-Methyl-2-mercapto1. Compound [1
01] on the 11th floor. NMR(CI)CJ 8): δo, I 3 (6
IT, s), Q. 90 (911,81,1,17 and], 35 C9 Summer 1.2Xs)-4,11) and 4.13 (311,2
×S), 4.60 (211, S (broad)),
5.45 and 5.87 (211,2×S (Broad 1), 7.5-8.1 (15T1, m), etc. (D and other R
"Unable to belong":-IR (clIcJa): 1740an
-1630z '[12'':] Compound []O'] 142Wl to toluene 7.5wl
Add iC and heat at 70°C for 4 hours. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel to give compound r12'l). NMRlCDC15): δ0.07(61(,S), 0
゜88 (9H, s), 1.1~1,3 (3H, d
), 1.23 C9H,s ), 10-3.2 (
I H-m), 108 (2H=d (broad), J=9Hz), 395 (3H-s), 8.9
~4.4 (2H, m), 4゜48 (2H=
s (broad)), 5.88 (2H1S
(Broad)) Example 7 Synthesis of Compound 11 + [+43 Co 21'
MI (Compound C8 of Example 4) 4.81 OTH[' 120
In yst, the presence of 1.2 ml of I':t aN, P
-methoxypencyl glyoxole-1-'I hydrate 44
Reacts with FI (Example 4-2)
The compound "91" in which the carboxylic acid 1-protecting group is substituted with PMB in the compound described in [2] is converted to 5-methyl-2-mercapto-1,3,4-thiadiazole. Compound [13] is obtained in the same manner as in Examples 4-3) to 4) except that 2-mercapto-1°3.4-thiadiazole is used instead of 2-mercapto-1°3.4-thiadiazole. NMR (CDCIB): δ1.08 (3H -d
r broad) - J = 6Hz), 8.80 (3H
-s)-4,15(2H=s(broad'l
), 4.88 (2H,s(broad"I'
I, 7.2-8.0 (15H, m), 8
゜97 (IHL S) I R (CHCI!a): 3480 tyn' (broad), 1 7 4 0 ff, 1 6
] 5 CJn 'C36) CO2I'MII CO2I'M13 [14] Compound r 13 ]511 (1719 to toluene 35
The mixture was heated at 70° C. for 11 hours at +51+, and after the reaction was completed, the solvent was distilled off under reduced pressure and the residue was subjected to silica gel chromatography. 64 μ of compound []3] are recovered and the target compound [14] is obtained. Revenue: 97,
125Nlf/NMR(CI)Cls): δ1.28 (31,1
,cl, J=6117,'l, 2.9~3.3 (I
II, m), 3.04M2H1d (broad), J
=911zl, 8.77 (3H1s), 3.9~4
．． 4 (21+, ITI)−4,3Pi (d) and 4.64 rd) (211,,1= 1311z−
'A11q), 5.18 (2H=s (broad)), 6.79 (d) and 7.29 (d
) (4H-J=9Hz-ABq), 8°97TIH
,s') IRrcHcl:8): 3600-330011ff
+ , 1 1780t7n , 1720z , 1615a'
UV (in MeCN): 224 nm (!: ~15,
000) -275 (ε: ~7,000), 281 nm
(ε: ~6,90(1), 290 (ε: ~6,000
) [15] 143■ anhydrous aluminum chloride, 4 ml of anisole
Dissolved in a mixed solvent of 0.6 ml of methylene chloride and -5
Cool to 0°C. To this mixture, compound [14, J l
20 '19 Ayunol 4 resistance and methylene chloride 061
Add the solution dissolved in No. 11 and stir for 35 minutes. Add 405 da of hydrogen to this mixture and 16 ml of water.
Add 1 liter of a solution dissolved in 100 ml of water with vigorous stirring, then add 20 ml of methylene chloride, and heat to room temperature.
l-ru. The anti-LIS mixture was passed through Hyflow once, and the aqueous layer was washed three times with diluted dichloromethane and then washed with I-IP-20 (2 times).
゜2 Cm x 8 an ) and desalinate. Elute with water, collect fractions containing compound % (C15),
Compound [15] was obtained by concentrating under reduced pressure and drying.
〕of? t). Collection Jet 3 (1#I/l'I IL
(Kllr): 340 (l al (7o-
), 1 7fiOz, 1600oノ!
'LJV (0,01M phosphoric acid weak f;To (pH7,+
1) In liquid): 275 nm (ε: ~ 12.0001 Patent applicant j1^ Nogi Pharmaceutical Co., Ltd. Agent Patent attorney Aoyama Ao and 1 other person (3≦)
) 567-

Claims (1)

[Claims] 1. Formula: [In the formula, X is an oxygen atom or a sulfur atom, Y is a hydrogen atom or a hydroxyl group that may be protected, Z is a hydrogen atom,
A protecting group for an alkali metal atom or a carboxyl group, R represents a heterocyclic group which may be substituted with a 4-pyridyl group or a low R-y alkyl group].