Dihydrotriazinylthiomethyl-oxacephem compounds represented by the formula: ##STR1## wherein A is amino or substituted amino; COB is carboxy, protected-carboxy or a carboxy salt; E is hydrogen or methoxy; M is hydrogen or hydroxy-protecting group; and R is lower alkyl are useful as antibacterial agents.

DETAILED DESCRIPTION OF THE INVENTION 
This invention relates to potent antimicrobial agents, dihydrotriazinyl 
compounds represented by the formula (I): 
##STR2## 
wherein A is amino or substituted amino; COB is carboxy, protected-carboxy 
or a carboxy salt; E is hydrogen or methoxy; M is hydrogen or 
hydroxy-protecting group; and R is lower alkyl. 
1-Dethia-1-oxacephalosporin compounds are described in Japanese Unexamined 
Patent Publication No. 49-133546, Japanese Unexamined Patent Publication 
No. 51-149295 and the corresponding chemical literature, but compounds 
involving hydro-aromatic ring, 
1-alkyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazine moiety at the 
3-position of 1-dethia-1-oxacephem structure have not yet been known. The 
inventors prepared dihydrotriazine compounds, investigated their 
antibacterial activity, and found that these exhibited remarkable 
properties in antimicrobial action, absorption, excretion and the like. 
This invention was completed based on this finding. 
[I] Structure of dihydrotriazine compounds 
Dihydrotriazine compounds (I) in this invention are derivatives of 
1-dethia-1-oxa-3-(1-alkyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)t 
hiomethyl-3-cephem-4-carboxylic acids represented by the formula (I) and 
have amino or substituted amino, and hydrogen or methoxy at the 7 
position. The carboxy group at the 4 position may be protected. 
The explanation of each group in a structure of dihydrotriazine compounds 
are as follows: 
[1] Amino or substituted amino represented by A 
Substituted amino means those at the side chain of natural or synthetic 
penicillins and cephalosporins and include organic or inorganic acyl 
amino, diacylamino, hydrocarbylamino, sulfenylamino, silylamino and acid 
addition salts with the amino group. 
Representative of acyl groups involved in the substituted amino described 
above are acyl of carbonic acid (e.g. alkoxycarbonyl, aralkoxycarbonyl, 
aryloxycarbonyl), acyl of sulfuric acid, acyl of phosphoric acid (e.g. 
dialkoxyphosphinyl, dialkoxythiophosphonyl, alkoxyaminophosphoroyl), and 
the other inorganic acyl; alkanoyl, cycloalkanoyl, aralkanoyl, aroyl, 
alkylsulfonyl, arylsulfonyl, aralkylsulfonyl and the other organic acyl. 
These groups, if possible, may have a hetero atom or atoms in the main 
chain, unsaturation, or substituents as halogen (e.g. fluorine, chlorine, 
bromine), nitrogen group (e.g. amino, hydrazino, azido, alkylamino, 
arylamino, acylamino, alkylideneamino, acylimino, nitro), oxygen group 
(e.g. hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy, oxo), sulfur group 
(e.g. mercapto, alkylthio, aralkylthio, arylthio, acylthio, thioxo, sulfo, 
sulfonyl, sulfinyl, alkoxysulfonyl, aryloxysulfinyl), carbon group (e.g. 
alkyl, alkenyl, aralkyl, aryl, carboxy, carboalkoxy, carbamoyl, alkanoyl, 
aroyl, aminoalkyl, araalkanoyl, cyano) and phosphorus group (e.g. phospho, 
phosphoroyl). Acyl groups may also be diacyl groups derived from polybasic 
acids (e.g. phthaloyl, pyridine-2,3-dicarbonyl, maleoyl, succinoyl). 
Representative acyls of the acylamino groups are: 
(a) C.sub.1 -C.sub.10 alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, 
isobutyryl, valeryl, isovaleryl, pivaloyl, cyclohexylacetyl, octanoyl, 
decanoyl) or benzoyl; 
(b) halo-C.sub.1 -C.sub.4 alkanoyl (e.g. chloroacetyl, trifluoroacetyl, 
chloropropionyl, bromopropionyl, chlorobutyryl); 
(c) trifluoromethylthioacetyl or cyanoacetyl; 
(d) (2- or 4-pyridon-1-yl)acetyl or (2-iminothiazolin-4-yl)acetyl; 
(e) acyl groups represented by the formula: 
EQU Ar--CQQ'--CO-- 
wherein Q and Q' are hydrogen or methyl; Ar is a cyclic group such as 
phenyl, dihydrophenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, 
oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, 
thiatriazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, 
pyrimidyl, pyrazinyl, pyridazinyl or triazinyl which cyclic groups can be 
substituted by halogen, lower alkyl (e.g. methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl), hydroxy, both halogen 
and hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, t-butoxy, 
methylenedioxy, ethylenedioxy), acyloxy (e.g. formyloxy, acetyloxy, 
propionyloxy, pentanoyloxy, carbamoyloxy, benzoyloxy, methoxycarbonyloxy, 
ethoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy, 
nitrobenzyloxycarbonyloxy, methoxybenzyloxycarbonyloxy), aralkyloxy (e.g. 
benzyloxy, methoxybenzyloxy, aminobenzyloxy, methylbenzyloxy, 
isopropylbenzyloxy, nitrobenzyloxy, diphenylmethoxy, phthalidyloxy), 
aryloxy (e.g. phenoxy, tolyloxy, xylyloxy, indanyloxy), amino, acylamino 
(e.g. C.sub.1 -C.sub.10 alkanoylamino, lower-alkanesulfonylamino), 
hydroxymethyl, aminomethyl or the like; 
(f) acyl groups represented by the formula: 
EQU Ar--G--CQQ'--CO-- 
wherein Ar, Q and Q' are the same as mentioned above and G is oxygen or 
sulfur; 
(g) acyl groups represented by the formula: 
EQU Ar--CHT--CO-- 
wherein Ar is the same as mentioned above; T is (i) hydroxy or acyloxy as 
described above; (ii) carboxy, carboxy protected by lower alkoxy, aralkoxy 
or aryloxy as described above, cyano, or carbamoyl; (iii) sulfo or lower 
alkoxysulfonyl; 
(h) acyl groups represented by the formula: 
EQU L--O--CO-- 
wherein L is t-butyl, 1,1-dimethylpropyl, cyclopropylmethyl, 
1-methylcyclohexyl, isobornyl, ethoxy-t-butyl, 2-alkanesulfonylethyl, 
2,2,2-trichloroethyl, benzyl, methoxybenzyl, nitrobenzyl, aminobenzyl, 
diphenylmethyl, tolylmethyl, phenyl, xylyl or pyridylmethyl; 
(i) acyl groups represented by the formula: 
##STR3## 
wherein Ar is the same as mentioned above; W is hydrogen, C.sub.1 
-C.sub.10 alkanoyl or halo-C.sub.1 -C.sub.4 alkanoyl, or a group 
represented by the formula: Ar--CQQ'--CO-- (as mentioned above), Ar--CO--, 
LOCO--, 
##STR4## 
R.sup.1 NHCONR.sup.2 --CO--, R.sup.1 NHCSNR.sup.2 CO--, 
##STR5## 
wherein Ar and L are as defined above, and R.sup.1 and R.sup.2 are 
hydrogen, C.sub.1 -C.sub.4 alkyl (e.g. methyl, ethyl, propyl, t-butyl) or 
C.sub.1 -C.sub.10 alkanoyl; or W is an enolic group of active carbonyl 
compounds represented by the formula 
##STR6## 
wherein R.sup.1 and R.sup.2 are the same as mentioned above; or NHW is 
diacylamido such as phthalimido or succinimido; 
(j) acyl groups represented by the formula: 
##STR7## 
wherein Ar and R.sup.1 are the same as mentioned above; (k) 5-aminoadipoyl 
in which the carboxy or amino group is optionally protected with a 
conventional carboxy or amino protecting group. Substituted amino may be 
diacylamino derived from C.sub.4 to C.sub.10 polybasic acids. 
Representative substituents in the hydrocarbonated amino are hydrocarbyl 
such as 1-carbethoxy-1-propen-2-yl, 1-carbamoyl-1-propen-2-yl, 
1-N-phenylcarbamoyl-1-buten-2-yl, 1-propen-2-yl, 1-phenylpentene-2-yl, 
methyl, t-butyl and trityl, and univalent or bivalent hydrocarbon group 
such as methylidene, ethylidene, 1-halo-2-phenylethylidene, 
1-methoxybenzylidene, 1-chlorobenzylidene, 
1-loweralkoxy-2-phenylethylidene, 1-loweralkoxy-2-phenoxyethylidene and 
di-t-butyl-4-hydroxybenzylidene. 
Organic silyl (e.g. trimethylsilyl, methoxydimethylsilyl, 
dimethoxymethylsilyl) and organic stannyl (e.g. trimethylstannyl) are also 
conventional amino protecting groups. 
Substituted amino A includes a group convertible into amino or amido such 
as azido, isocyanato and isocyano. 
The group A containing highly reactive part may be protected for purpose of 
preparation or preservation. When Compounds (I) are intermediates, the 
structure of them are widely variable, because the group A can be 
converted into the amino group and then the amino replaced with the 
desirable A group. Particularly, groups represented by the formula: 
##STR8## 
or the esters thereof and groups represented by the formula: 
##STR9## 
are important. [2] Carboxy or protected carboxy COB 
Carboxy protecting groups include ones ordinarily used in the field of 
penicillin and cephalosporin chemistry for temporary protection of carboxy 
group. Representative of them are esters such as alkyl esters (e.g. 
methyl-, ethyl-, trichloro-ethyl-ester), haloalkyl esters (e.g. 
chloroethyl-, 2-bromoethyl-, 2-iodoethyl-, 2-bromopropyl- ester), 
acylalkyl ester (e.g. phenacyl-, 4-chlorophenacyl- ester), alkoxyalkyl 
esters (e.g. methoxymethyl, 1-methoxyethyl-, ethoxymethyl- ester), 
acyloxyalkyl esters (e.g. acetoxymethyl, 1-acetoxyethyl, 
pivaloyloxymethyl-, 1-pivaloyloxyethyl-, ethoxycarbonyloxymethyl- and 
phthalidyl- ester), aralkyl esters (e.g. benzyl-, methoxybenzyl-, indanyl, 
nitrobenzyl-, diphenylmethyl-, trityl- ester), aryl esters (e.g. phenyl-, 
naphthyl- ester), metalic esters (e.g. trimethylsilyl, trimethyltin- 
ester) and like esters, acid anhydrides, thiol esters, amides, hydrazides, 
azides and the like carboxy derivatives. These carboxy derivatives, when 
possible, may involve above-mentioned halogen atoms, sulfur-, oxygen-, 
nitrogen-, carbon- group, and other substituents or may involve 
unsaturated bond. 
Among these carboxy derivatives, ones having groups which are stable in 
reaction medium and which can be removed without any undesired change in 
other parts of the molecule after termination of the reaction, are 
important. Representatives of them are haloalkyl-, acylalkyl-, 
alkoxyalkyl-, acyloxyalkyl-, aralkyl-esters, and dialkylhydrazides. The 
group COB can also be a carboxy salt (e.g. sodium-, potassium-, 
magnesium-, aluminum-, alkylamine-salts). Pharmaceutically acceptable 
salts such as alkali metal salts and lower alkylamine salts are preferred. 
[3] Hydrogen or methoxy group E 
Regardless of structure E being hydrogen or methoxy, Compounds (I) exhibit 
potent antibacterial activity, but ones in which E is methoxy, are more 
stable against lactamase and exhibit a broad spectrum antibacterial 
activity. 
[4] Alkyl groups R 
R represents lower alkyls such as methyl, ethyl, propyl, isopropyl, butyl, 
isobutyl, pentyl, cyclohexyl, cyclopropylethyl, octyl and the like, 
preferably methyl. 
[5] Hydroxy-protecting groups M 
Hydroxy-protecting groups M are introduced for convenience of preparation 
or absorption and converted into hydrogen afterwards. The group M includes 
hydroxy-protecting groups ordinarily used in the field of penicillin or 
cephalosporin chemistry for protecting a hydroxy, for example, acyls (e.g. 
formyl, haloacetyl, oxalyl, the above-mentioned groups represented by the 
formula: L--OCO--), ethers (e.g. methoxymethyl-, ethoxymethyl-, 
tetrahydrofuranyl-, tetrahydropyranyl-, t-butyl-, 2-hydroxy-t-butyl- 
ethers), and silyl groups (e.g. trimethylsilyl, methoxydimethylsilyl, 
ethylenedioxymethylsilyl). 
Dihydrotriazines compounds (I) of this invention include the following 
compounds and the pharmaceutically acceptable salts thereof listed in 
Table. 
##STR10## 
provided that the compounds of Nos. 13, 14 and 15 possess the following 
configuration: 
##STR11## 
__________________________________________________________________________ 
A E M R COB 
__________________________________________________________________________ 
1 H.sub.2 N H H CH.sub.3 
COOCHPh.sub.2 
2 " " COOC.sub.4 H.sub.9 -t 
" 
3 " " H C.sub.2 H.sub.5 
COOCH.sub.2 CCl.sub.3 
4 " " " C.sub.3 H.sub.7 
COOCH.sub.2 Ph 
5 PhCH.sub.2 CONH " 
##STR12## CH.sub.3 
COOCHPh.sub.2 
6 " " " " 
##STR13## 
7 " " H " " 
8 " " " " COOH 
##STR14## " " " " 
10 
##STR15## " " " " 
11 
" " " " COOCHPh.sub.2 
12 
##STR16## " " " COOH 
13 
.alpha.PhCONH .beta.H 
" " " 
14 
##STR17## " 
##STR18## " 
##STR19## 
15 
##STR20## " " " " 
16 
##STR21## H H " COOH 
17 
##STR22## " " " COOCHPh.sub.2 
18 
" " COOC.sub.4 H.sub.9 -t 
" 
##STR23## 
19 
##STR24## " H " COOH 
20 
##STR25## " " " " 
21 
##STR26## " " " " 
22 
##STR27## " " " " 
23 
##STR28## " " " " 
24 
##STR29## " " " " 
25 
##STR30## " " " " 
26 
##STR31## " " " " 
27 
##STR32## " " " " 
28 
##STR33## " " " " 
29 
" " " " 
##STR34## 
30 
##STR35## " " " COOH 
31 
##STR36## " " " " 
32 
HCHO " " " " 
33 
CF.sub.3 SCH.sub. 2 CONH 
" " " " 
34 
NCCH.sub.2 CONH " " " " 
35 
PhOCH.sub.2 CONH " " " " 
36 
##STR37## " " " " 
37 
##STR38## " " " " 
38 
PhCH.sub.2 OCONH " " " " 
39 
##STR39## " 
##STR40## " COOCH.sub.2 Ph 
40 
Cl.sub.3 CCH.sub.2 OCONH 
" " " " 
41 
H.sub.2 N CH.sub.3 O 
H " COOH 
42 
" " " " COOCH.sub.2 Ph 
43 
" " " " COOCHPh.sub.2 
44 
" " " " 
##STR41## 
45 
" " COOC.sub.4 H.sub.9 -t 
" " 
46 
" " " " COOCH.sub.2 Ph 
47 
" " H C.sub.2 H.sub.5 
COOCH.sub.2 Ph 
48 
" " " C.sub.3 H.sub.7 
COOCH.sub.2 Ph 
49 
HCONH " " CH.sub.3 
COOH 
50 
CF.sub.3 SCH.sub.2 CONH 
" " " " 
51 
NCCH.sub.2 CONH " " " " 
52 
##STR42## " " " " 
53 
##STR43## " " " " 
54 
" " " " COOCHPh.sub.2 
55 
BrCH.sub.2 COCH.sub.2 CONH 
" " " " 
56 
PhCH.sub.2 CONH " " " " 
57 
" " " " COOH 
58 
##STR44## " " " " 
59 
" " " " COOCH.sub.2 Ph 
60 
##STR45## " " " " 
61 
" " " " COOH 
62 
##STR46## " " " " 
63 
##STR47## " " " " 
64 
##STR48## " " " COOCH.sub.2 Ph 
65 
" " " " COOCHPh.sub.2 
66 
PhOCH.sub.2 CONH " " " COOCH.sub.2 Ph 
67 
" " COOC.sub.4 H.sub.9t 
" COOCHPh.sub.2 
68 
" " " " 
##STR49## 
69 
##STR50## " H " COOCH.sub.2 Ph 
70 
##STR51## CH.sub.3O 
" " COOH 
71 
##STR52## " " " " 
72 
##STR53## " " " " 
73 
##STR54## " " " " 
74 
##STR55## " " " " 
75 
##STR56## " " " " 
76 
##STR57## " " " " 
77 
##STR58## " " " COOCHPh.sub.2 
78 
##STR59## " " " " 
79 
##STR60## " " " " 
80 
##STR61## " " " COOH 
81 
##STR62## CH.sub.3 O 
" " " 
82 
##STR63## " " " " 
83 
##STR64## " " " " 
84 
##STR65## " " " COOCHPh.sub.2 
85 
##STR66## " " " " 
86 
##STR67## " " " " 
87 
##STR68## " " " " 
88 
##STR69## " " " " 
89 
##STR70## " " " " 
90 
##STR71## " " " " 
91 
##STR72## " " " " 
92 
##STR73## " " " " 
93 
PhCH.sub.2 OCONH " " " COOCH.sub.2 Ph 
94 
##STR74## " " " COOCHPh.sub.2 
95 
Cl.sub.3 CCH.sub.2 OCONH 
" " " " 
__________________________________________________________________________ 
[II] Use, Dosage and Antibacterial Activity 
Compounds (I) exhibit potent antibacterial activity and are useful as 
antibacterial agent for human, animals or plants. Compounds (I) may be 
administered to human or warm-blood animals, for example at a daily dose 
of 0.1-10 mg per 1 kg of body weight orally or parenterally in a 
conventional manner. Particularly, pharmaceutically acceptable carboxy 
salt of Compounds (I) may be administered in a form of solution by means 
of intravenous injection, intramuscular injection or subcutaneous 
injection. Compounds (I) may be put in ampoules in a form of solution, or 
preferably those are enclosed in ampoules in forms of crystals, powder, 
microcrystals, lyophilizate or the like and administered as a solution 
immediately before use. 
Compounds (I), wherein A is arylglycylamino or pharmaceutically acceptable 
esters of arylmalonylamino, such as indanyl-, alkanoyloxymethyl-, 
alkoxycarbonyloxymethyl-, phenacyl-, substituted phenacyl-, phthalidyl- 
and aryl-esters can orally be absorbed, so those may be administered 
orally to human or animals in forms of powder, tablets, granules, 
capsules, troches, dry syrups, suspensions, solutions, emulsions, 
inhalants or the like. Further, those may be administered as 
suppositories, eye lotion, powder for topical use, ointments or the like. 
Unit dosage forms such as tablets, capsules, ampoules, vials and the like 
are most preferable. These formulations also provide a method for treating 
infections caused by bacteria sensitive to the compounds of this 
invention. Compounds (I) of this invention are ordinarily administered at 
a dose of 1-40 mg/kg a day for injection or 10-400 mg/kg a day for oral 
administration, or 1 .mu.g-1 mg a day for topical application, the dosage, 
however, can be increased or decreased in accordance with sensitivity of 
bacteria, times of administration, condition of patient and the like. 
Dihydrotriazine Compounds (I) are up to about 32 times as strong as the 
corresponding dihydrotriazinyl cephalosporins in vitro antibacterial 
activity, so those are potent antibacterial agent against gram positive 
and negative bacteria. The protective effect against infections caused by 
Escherichia coli in vivo are generally 1-4 times as effective as the 
corresponding 1-methyl-tetrazol-5-ylthio-1-dethia-1-oxacephalosporins. 
Compounds (I) are further effective against bacteria practically resistant 
to commercially available cephalosporins, for example, Enterobacter, 
Serratia, indole-positive Proteus, and the like at the same level of MIC 
against sensitive bacteria (e.g. MIC less than 10 .gamma./cc). 
[III] Preparation 
Dihydrotriazine Compounds (I) may be prepared, for example, in the 
following manner. 
(1) Cyclization 
2-Oxoazetidine Compounds (II) may be cyclized by heating to yield 
Dihydrotriazine Compounds (I) as shown in the following reaction scheme. 
##STR75## 
This reaction may be carried out by heating at about 70.degree. to 
150.degree. C. for several hours in an inert solvent such as toluene, 
xylene, methylene chloride, dioxane, tetrahydrofuran and the like. 
The compounds having phosphonyl group in place of arylphosphoranylidene 
group may also be cyclized on treatment with bases to yield the objective 
ones, and the 
2-oxo-4-hydroxy-1-[.alpha.-carboxy-.beta.-(1-methyl-5-hydroxy-6-oxo-1,6-di 
hydro-1,3,4-triazin-2-yl)thiomethyl-.gamma.-halopropyl]azetidine 
derivatives may be cyclized on dehydrohalogenation reaction to yield the 
object ones. 
(2) Substitution Reaction at Amino group 
Compounds (I) wherein A is acylamino may be prepared from the compounds 
wherein A is amino on treatment with the reactive derivatives having the 
desirable acyl groups (e.g. halogenides, anhydrides, reactive esters, 
reactive amides, azides) in a conventional manner. The following examples 
are provided to illustrate the acylations according to the classification 
of the species of the reactive derivatives. 
(i) Free acids 
Compounds (I) wherein A is amino are reacted with 1 to 2 molar equivalent 
of free acids in the presence of 1 to 2 molar equivalent of condensing 
agent such as carbodiimides (e.g. N,N'-diethylcarbodiimide, 
N,N'-dicyclohexylcarbodiimide), carbonyl compounds (e.g. 
carbonylimidazoles), isoxazolinium salts, acylamino compounds (e.g. 
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) and the like, preferably 
in a solvent not having active hydrogen such as halogenated hydrocarbons, 
nitriles, ethers, amides, their mixture or the like. 
(ii) Acid anhydrides 
Acid anhydrides include symmetric anhydrides, mixed anhydrides [e.g. mixed 
anhydrides of mineral acids and particularly alkyl- or 
aralkyl-hemicarbonate; mixed anhydrides of mineral acids and alkanoic 
acids or sulfonic acids], intramolecular anhydrides (e.g. ketones, 
isocyanates) and the like acid anhydrides. 
Compounds (I) wherein A is amino are reacted with 1 to 2 molar equivalents 
of acid anhydrides in the presence of 1 to 10 molar equivalents of acid 
acceptor such as inorganic bases (e.g. oxide, hydroxide, carbonate, 
bicarbonate and the like of alkali metals and alkaline earth metals), 
organic bases (e.g. tetriary amines, aromatic bases), oxiranes (e.g. 
alkyleneoxides, aralkyleneoxides) or the like, preferably in a solvent not 
having active hydrogen such as halogenated hydrocarbons, nitriles, ethers, 
amides, their mixtures or the like. 
(iii) Acid halogenides 
Compounds (I) wherein A is amino are reacted with 1 to 2 molar equivalents 
of acid halogenides, preferably in the presence of 1 to 10 molar 
equivalents of aforementioned acid acceptor in a solvent such as 
halogenated hydrocarbons, nitriles, ethers, ketones, water, dialkylamides, 
their mixtures and the like. 
(iv) Reactive esters 
Reactive esters include enolic esters (e.g. vinyl esters, isopropenyl 
esters), aryl esters (e.g. halophenyl esters, nitrophenyl esters), 
heterocycle-aromatic esters (e.g. esters with 1-hydroxybenzotriazole), 
esters with oxime, esters, with diacylhydroxyamine and the like esters of 
which acyl part is a desirable acyl group. 
(v) Reactive amides 
Aromatic amides (e.g. amides with imidazole, triazole, 
2-ethoxy-1,2-dihydroquinoline), diacylanilide and the like are included. 
(vi) O-Acylformamide compounds 
For example, O-enolic ester salts of N,N-dimethylformamide are included. 
(vii) Other reactive derivatives 
More than 1 mole of the compounds described in (iv)-(vi) may be reacted in 
an aforementioned solvent not having active hydrogen or their mixture. 
Any reactions described above may be carried out at about -50.degree. to 
100.degree. C., preferably at -20.degree. to 50.degree. C. A reaction 
solvent may optionally be selected from the group consisting of 
halogenated hydrocarbons (e.g. methylene chloride, chloroform, 
dichloroethane, trichloroethane, chlorobenzene), ethers (e.g. diethyl 
ether, tetrahydrofuran, tetrahydropyran, anisole), ketones (e.g. acetone, 
methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, acetophenone), 
esters (e.g. ethyl acetate, butyl acetate, methyl benzoate), 
nitrohydrocarbons, nitriles (e.g. acetonitrile, benzonitrile), amides 
(e.g. formamide, acetamide, dimethylformamide, dimethylacetamide, 
hexamethylphosphorotriamide), sulfoxides, acids (e.g. formic acid, acetic 
acid), bases (e.g. butylamine, triethylamine, pyridine, picoline, 
quinoline), water and the like. 
If required, the reaction may be promoted by stirring under innert gas 
while removing moisture. 
(Introduction of the other substituents of amino) 
The desirable silyl group, sulfenyl group, or hydrocarbon group may be 
introduced on action of the corresponding silylating agent such as silyl 
halogenide (e.g. trimethylsilyl chloride, methoxydimethylsilyl chloride, 
methylenedioxysilyl chloride) and silazane (e.g. hexamethylsilazane, 
bistrimethylsilyl acetamide), sulfenylating agent such as halogenated 
sulfenyl (e.g. O-nitrophenylsulfenyl chloride) or hydrocarbonating agent 
such as aldehydes (e.g. salicylic aldehyde) and ketones (e.g. 
acetoacetate, acetoacetamide) in a conventional manner. 
Compounds (I) wherein A is amide are reacted with an enolic halogenating 
agent such as phosphorus pentachloride and the like to yield the compounds 
wherein A is 1-haloalkylideneamino, and the latter treated with alcohol to 
yield the compounds wherein A is alkoxyalkylideneamino. 
In the aforementioned reactions (1) and (2), the amino group A may 
preliminarily be protected or activated in forms of iminohalides, 
iminoethers, isocyanates, enamines and the like. 
(3) Removal of substituent of amino 
Compounds (I) wherein A is free amino may be prepared from ones wherein A 
is substituted amino on action of solvolyzing agent, hydrogenolyzing 
agent, reducing agent or the like in a conventional manner. For example, 
Compounds (I) wherein A is amino may be prepared: by reaction with 
hydrazine, phosphorus pentachloride and alcohols, carbonium ion forming 
agents or the like, when the substituent of amino is acyl; by reduction or 
on treatment with Lewis acids such as aluminum chloride, when the 
substituent is alkoxycarbonyl or haloalkoxycarbonyl; on treatment with 
acids, when the substituent is silyl; or on treatment with bases, when the 
substituent is sulfenyl. 
(4) Introduction of carboxy protecting group 
Compounds (I) having a free carboxylic acid may be converted into these 
having a protected carboxy group in conventional manner such as 
esterification by alcohols and condensing agents, diazo compounds, 
halogenated hydrocarbons, silyl or stannyl compounds; salt formation by 
bases; hydrazido formation by hydrazine; anhydride formation by acid 
halogenides and bases; and the like. 
(5) Removal of carboxy protecting group 
Carboxy protecting groups may be removed in manner usually used in the 
field of penicillin and cephalosporin chemistry. For example, the 
following methods may be employed: 
(i) Highly active esters, amides or anhydrides are hydrolyzed on treatment 
with water containing acids, bases or buffers. 
(ii) Haloethyl-, benzyl-, nitrobenzyl-, methylbenzyl-, dimethylbenzyl-, 
diarylmethyl-, triarylmethyl-esters are mildly reduced in conventional 
manner such as by tin, zinc, chromic salt or the like and acids, or sodium 
dithionite, or catalytically hydrogenated in the presence of platinum, 
palladium, nickel or the like to yield the corresponding free carboxylic 
acids. 
(iii) Benzyl-, methoxybenzyl-, methylbenzyl-, dimethylbenzyl, t-alkyl-, 
trityl-, diarylmethyl-, cyclopropylmethyl-, cyclopropylethyl-, 
sulfonylethyl-esters are converted into the corresponding free carboxylic 
acids on solvolysis by mineral acids, Lewis acids, sulfonic acids, 
strongly acidic carboxylic acids or the like, and if required, in the 
presence of cation acceptor such as anisole, phenol, thiophenol and the 
like. 
(iv) Phenacyl-, ethinyl-, p-hydroxy-3,5-di-t-butylbenzyl esters are 
converted into the corresponding free carboxylic acids on hydrolysis in 
the presence of bases. 
(6) Introduction of the methoxy group 
Compounds (I) wherein E is methoxy may be prepared from those wherein E is 
hydrogen, for example, in the following manner: 
(i) Compounds (I) wherein E is hydrogen are reacted with N-halogenating 
agent (e.g. hypohalite such as t-butylhypochlorite), alkali metal 
methoxide (e.g. lithium methylate, sodium methylate, potassium methylate) 
and reducing agents in methanol; 
(ii) Compounds (I) wherein E is hydrogen are reacted with 
t-butylhypochlorite and methanol-base in the presence of N-lithium 
introducing agent such as phenyl lithium in a solvent such as 
tetrahydrofuran, and if required, followed by reduction; 
(iii) Compounds (I) wherein E is hydrogen are reacted with 
t-butylhypochlorite in the presence of sodium borate in methanol and 
by-product, N-chloro compounds, is reduced by zinc, phosphite or the like; 
(iv) Compounds (I) wherein E is hydrogen and A is aralkylideneamino are 
reacted with oxidizing agent and methylmercaptan, and then mercuric 
acetate-methanol, 
(v) Compounds (I) wherein E is hydrogen and A is p-hydroxyaralkylideneamino 
are reacted with oxidizing agent and then methanol; 
(vi) Compounds (I) wherein E is hydrogen and A is isonitrile are reacted 
with oxidizing agent and methanol; and 
(vii) Compounds (I) wherein E is hydrogen and A is 
.alpha.-haloalkanoylamino is reacted with bromine-DBU or phosphorus 
pentachloridepyridine to yield the corresponding iminohalide compounds, if 
required, the latter reacted with trialkylsilylhalide or 
tetraalkylammonium halite and then base to yield the corresponding 
conjugated imino compounds, and the latter treated with methanol. 
(7) Introduction of 
1-alkyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-ylthio group 
7.beta.-Substituted-amino-1-dethia-1-oxa-3-cephem-4-carboxylic acid 
derivatives having methyl substituted by leaving group at the 3 position 
are reacted with heterothiol salts having the above hetero thio group to 
yield the objective compounds (I). Examples of the leaving groups are 
those replaceable with the desired hetero-thio groups, such as halogens, 
alkanoyloxy, haloalkanoyloxy, sulfonyloxy and the like. 
This reaction is carried out in a conventional manner, for example, if 
required, on addition of reaction accelerator such as bases in a solvent. 
(8) Removal of hydroxy protecting group 
Hydroxy protecting groups M may be selected from the groups which are 
readily removable without any undesired influence on other parts of the 
molecule. For example, carbonate such as t-butoxycarbonyl, 
benzyloxycarbonyl, dimethylbenzyloxycarbonyl, isobornyloxycarbonyl, 
trichloroethoxycarbonyl, sulfonylethoxycarbonyl, and 
cyclopropylmethoxycarbonyl, tetrahydropyranyl, active ether such as 
1-alkoxycyclopentyl and methoxymethyl, and the like may be removed with 
acids. 
Hydroxy protecting group M is introduced for convenience of synthesis or 
use, and replaced by hydrogen afterwards. 
(9) Transformation of acyl group 
Substituted amino of dihydrotriazine compounds (I) may be modified for 
protection of unstable group in reaction media, recovered afterwards, or 
for enhancement of antibacterial activity, or the like. 
This reaction includes, for examle, acylation of hydroxy or amino, 
transformation of protected carboxy, benzyloxycarbonylamino and 
t-butoxycarbonylamino into free carboxy or amino, formation of 
aminothiazole ring by reaction of .omega.-haloacetoacetyl group with 
thiourea, and the like, which may be carried out in a well-known method. 
Each reaction mentioned above may be carried out according to known unit 
process, for example, in a solvent under cooling or heating, if required, 
with stirring under innert gas. 
The products may be isolated by means of extraction, washing, drying, 
adsorption, evaporation or the like, and purified by reprecipitation, 
crystalization, chromatography or the like. 
More than two of the suitably selected reactions may be carried out at the 
same time. 
[IV] Preparation of starting materials 
Dihydrotriazine Compounds (I) in this invention may also be prepared, for 
example, in the manner as shown in the following FIG. 1 and FIG. 2. 
FIG. 1 
(Japanese Unexamined Patent Publication No. 52-65292) 
##STR76## 
(wherein Hal is halogen; Ar is aryl, typically phenyl; A, COB, E, M, and R 
are the same as mentioned above) 
FIG. 2 
(Japanese Unexamined Patent Publication No. 52-65292) 
##STR77## 
(Preferably M is hydroxy-protecting group such as t-butoxycarbonyl, 
isobornyloxy carboxy or the like in the reaction medium, and then 
converted into hydrogen afterwards.) 
(wherein A, Ar, COB, E, Hal and M are the same as mentioned above) 
These reactions are carried out according to the manner described in 
Japanese Unexamined Patent Publication No. 51-149295 and No. 52-65292. 
Representatives of them are concretely described in the following 
Preparations.

The following examples are provided to further illustrate this invention. 
Ph means phenyl group. Physical data for the compounds prepared 
hereinbelow are summarized in the tables following the reported examples 
and preparations. 
EXAMPLE 1 (CYCLIZATION) 
(1) A solution of 10.35 g of diphenylmethyl 
.alpha.-[3.beta.-phenylacetamide-3.alpha.-methoxy-4.beta.-{3-(1-methyl-5-h 
ydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thio-2-oxopropyl}-oxy-2-azetidi 
n-1-yl]-.alpha.-triphenylphosphoranyldeneacetate in 200 ml of dioxane is 
refluxed for 6 hours under heating and evaporated under reduced pressure. 
The residue is purified by chromatography on a column of 250 g of silica 
gel to yield 3.85 g of diphenylmethyl 
7.beta.-phenylacetamido-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-d 
ihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate 
in 52.7% yield. 
IR:.nu..sub.max.sup.CHCl.sbsp.3 1783, 1710, 1690, 1590 cm.sup.-1 
(2) The following compounds are prepared in a procedure analogous to above 
(1). 
__________________________________________________________________________ 
(RCH.sub.3) 
A E M COB 
__________________________________________________________________________ 
##STR78## .alpha.H 
H COOCHPh.sub.2 
2 " " 
##STR79## 
##STR80## 
3 
##STR81## " H COOCHPh.sub.2 
4 " .alpha.CH.sub.3 O 
H COOH 
5 
##STR82## " " COOCHPh.sub.2 
6 
##STR83## " " COOCH.sub.2 Ph 
__________________________________________________________________________ 
EXAMPLE 2 (Amidation) 
(1) To a solution of 1.8 mmoles of hemi-diphenylmethyl 
2-fluoro-4-hydroxyphenylmalonate in 6 ml of methylene chloride are added 
1.5 mmoles of triethylamine and 1.5 mmoles of oxalyl chloride under 
ice-cooling, and the mixture stirred for 1 hour, mixed with a solution of 
0.4 mmole of diphenylmethyl 
7.beta.-amino-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3 
,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate in 4 ml of 
methylene chloride containing 0.15 ml of pyridine under ice-cooling. The 
reaction mixture is stirred for 2.5 hours, poured into 5% aqueous 
phosphoric acid solution and extracted with ethyl acetate. The extract is 
washed with water, dried and evaporated. The residue is chromatographed on 
50 parts by volume of silica gel and eluted with a mixture of benzene and 
ethyl acetate (1:1) to yield 0.24 mmole of diphenylmethyl 
7.beta.-[.alpha.-(2-fluoro-4-hydroxyphenyl)-.alpha.-diphenylmethoxycarbony 
lacetamido]-7.alpha.-methoxy-3-(1-methyl-5 
-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3- 
cephem-4-carboxylate (60% yield). 
NMR: .delta..sup.CDCl.sbsp.3 (3.12s+3.15s)3H, 3.47s3H, 3.88brs2H, 
4.23brs2H, 4.97brs1H, 5.00ss1H, 6.23-7.73m25H. 
(2) When 0.8 ml of hemi-diphenylmethyl 3-thienylmalonate is employed in 
place of 1.8 mmoles of hemi-diphenylmethyl 
2-fluoro-4-hydroxyphenylmalonate in the above Examples, 0.17 mmole of 
diphenylmethyl 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-diphenylmethoxycarbonylacetamido]-7.a 
lpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)th 
iomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate is produced. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1785, 1720, 1715, 1695, 1590 cm.sup.-1 
(3) To a solution of 4.57 mmoles of diphenylmethyl 
7.beta.-amino-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)t 
hiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylte in 25 ml of acetonitrile is 
added 4.5 ml of bistrimethylsilylacetamide, and the mixture stirred at 
room temperature for 1 hour, and evaporated under reduced pressure. The 
residue is dissolved in tetrahydrofuran under ice-cooling, and mixed with 
a solution of active ester in tetrahydrofuran prepared from 4.57 mmoles of 
(4-hydroxyphenyl)-N-t-butoxycarbonylglycine, 4.57 mmoles of 
1-hydroxy-1H-benzotriazole and 5.48 mmoles of 
N,N'-dicyclohexylcarbodiimide. The reaction mixture is stirred at 
0.degree. for 20 minutes and at room temperature for 60 minutes, poured 
into ice water-ethyl acetate and shaken. The organic layer is separated, 
washed with water, dried and evaporated under reduced pressure. The 
residue is chromatographed on 120 g of silica gel, and eluted with a 
mixture of chloroform and methanol (97:3). The eluate is concentrated to 
yield 3.16 mmoles of diphenylmethyl 
7.beta.-[N-t-butoxycarbonyl-.alpha.-(4-hydroxyphenyl)glycineamido]-3-(1-me 
thyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin 
2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate. 
NMR: .delta..sup.CDCl.sbsp.3 1.43s9H, 3.37s3H, 5.03d(4 Hz)1H etc. 
(4) To a solution of 0.154 mmoles of diphenylmethyl 
7.beta.-amino-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3 
,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate in 1 ml of 
methylene chloride are added 15.6 mg of triethylamine at -40.degree. C. 
and then a solution of bromoacetoacetyl bromide (prepared from 0.013 ml of 
diketene) in methylene chloride, and the mixture allowed to stand at 
-40.degree. to -30.degree. C. for 60 minutes, mixed with 0.19 mmole of 
dimethylaniline and the same amount of bromoacetoacetyl bromide as 
mentioned above, and allowed to stand at -30.degree. to -40.degree. C. for 
30 minutes. The reaction mixture is diluted with 10% aqueous phosphoric 
acid solution and poured into ethyl acetate-ice water. The organic layer 
is washed with water, dried, and evaporated under reduced pressure to 
yield 132 mg of diphenylmethyl 
7.beta.-bromoacetamido-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-di 
hydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate. 
Rf=0.39 (silica gel TLC plate/ethyl acetate) 
EXAMPLE 3 (Removal of the amino-protecting group) 
(1) To a solution of 3.23 g of diphenylmethyl 
7.beta.-phenylacetamido-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-tria 
zin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate in 30 ml of 
methylene chloride are added 2.55 ml of N,N-dimethylaniline and 1.51 ml of 
trimethylchlorosilane, and the mixture stirred at room temperature for 1 
hour, mixed with 1.32 g of phosphorus pentachloride under cooling at 
-40.degree. C., stirred for 1.5 hours, mixed with 12 ml of methanol at 
-60.degree. C. and stirred at -60.degree. C. for 5 minutes and then at 
0.degree. C. for 30 minutes. The reaction mixture is treated in a 
conventional manner to yield 2.38 g of diphenylmethyl 
7-amino-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomet 
hyl-1-dethia-1-oxa-3-cephem-4-carboxylate as colorless powder in 90.5% 
yield. 
Rf=0.08 (silica gel plate/ethyl acetate) 
(2) In a manner similar to that of above (1), diphenylmethyl 
7.beta.-phenylacetamido-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-d 
ihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate 
(1.34 g) is treated with N,N-dimethylaniline and dimethyl silyl dichloride 
in methylene chloride to yield a compound having a protected hydroxy on 
its triazine ring and the product is treated with methanol to yield 0.98 g 
of diphenylmethyl 
7.beta.-amino-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3 
,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate as powder 
in 89% yield. 
Rf=0.21 (silica gel plate/ethyl acetate) 
(3) Diphenylmethyl 
7.beta.-phenylacetamido-3-(1-methyl-5-isobornyloxycarbonyloxy-6-oxo-1,6-di 
hydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate 
(129 mg) is treated with 37 mg of pyridine, 80 mg of phosphorus 
pentachloride and 1.5 ml of methanol in 5 ml of methylene chloride at 
-20.degree. C. in a similar manner to that mentioned above (1) to yield 99 
mg of toluene-p-sulfonate of the corresponding 7-free amino compound in 
73.5% yield. 
EXAMPLE 4 (Introduction of carboxy-protecting group) 
(1) The compounds having a free carboxy given in each of the examples are 
dissolved in dilute aqueous sodium hydrogencarbonate solution to yield the 
corresponding sodium salts and the latter examined antibacterial activity; 
the results indicate that the salts exhibit strong antibacterial activity 
against gram positive and negative bacteria. 
(2) 
7.beta.-[.alpha.-p-Hydroxyphenyl-N-(4-ethyl-2,3-dioxopiperazin-1-yl)carbon 
ylglycyl]amino-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3 
,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid (118 
mg) is dissolved in 3 ml of methanol and the insoluble materials are 
filtered off. The solution is diluted with 3 ml of ethanol and mixed with 
two equivalents of a solution of sodium 2-ethylhexanoate in isopropanol, 
and the precipitate collected by filtration and washed with ethanol, ethyl 
acetate and then ether to yield 49 mg of the corresponding sodium salts in 
54% yield. 
IR: .nu..sub.max.sup.KBr 1775, 1710, 1685 cm.sup.-1 
EXAMPLE 5 (Removal of the carboxy-protecting group) 
(1) To a solution of 148 mg of diphenylmethyl 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-diphenylmethoxycarbonylacetamido]-7.a 
lpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)th 
iomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate in 20 parts by volume of 
methylene chloride are added 4 parts by volume of anisole and 4 parts by 
volume of trifluoroacetic acid under ice-cooling, and the mixture stirred 
for 2 hours and evaporated under reduced pressure at room temperature. The 
residue is washed with ethyl ether to yield 77 mg of 
7.beta.-[.alpha.-(3-thienyl)-.alpha.-carboxyacetamido]-7.alpha.-methoxy-3- 
(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethi 
a-1-oxa-3-cephem-4-carboxylic acid as light yellow powder in 35% yield. 
IR: .nu..sub.max.sup.KBr 1783, 1710, 1586 cm.sup.-1 
(2) The following compounds may be prepared in a similar manner to that 
mentioned in (1) to (5). 
__________________________________________________________________________ 
(RCH.sub.3) 
A E M COB * 
__________________________________________________________________________ 
##STR84## H H COOH 
2 " OCH.sub.3 
" " 
3 
##STR85## H " " 
4 " OCH.sub.3 
" " 
5 
##STR86## H " " NBOC 
6 " OCH.sub.3 
" " " 
7 
##STR87## H " " 
8 " OCH.sub.3 
" " 
9 
##STR88## H " " 
10 
" OCH.sub.3 
" " 
11 
##STR89## H " " 
12 
" OCH.sub.3 
" " 
13 
##STR90## H H COOH 
14 
" OCH.sub.3 
15 
##STR91## OCH.sub.3 
" " NBOC 
16 
##STR92## " " " PCH.sub.3 OC.sub.7 H.sub.6 ester 
OCH.sub.3 OC.sub.7 H.sub.6 ether 
17 
##STR93## " " " OCHPh.sub.2 ester 
18 
##STR94## " " " OCHPh.sub.2 ester 
19 
##STR95## " " " OCHPh.sub.2 ester 
__________________________________________________________________________ 
* Protecting group in the side chain of the starting material (3) A 
solution of 110 mg of p-nitrobenzyl 7.beta.-phenyl 
acetamido-3-(1-methyl-5-isobornyloxycarbonyloxy-6-oxo-1,6-dihydro-1,3,4-tr 
iazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate in 
tetrahydrofuran-methanol (1:2) containing 0.03 ml of concentrated 
hydrochloric acid is shaken in the presence of 30 mg of 5% 
palladium-charcoal under hydrogen atmosphere for 4 7/12 hours, consuming 
15.14 ml of hydrogen gas. The mixture is filtered and the filtrate 
evaporated under reduced pressure. The residue is chromatographed on 1.5 g 
of silica gel and eluted with chloroform-ethyl acetate (3:1) to yield 68 
mg of 
7-.beta.-phenylacetamido-3-(1-methyl-5-isobornyloxycarbonyloxy-6-oxo-1,6-d 
ihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic 
acid in 74.3% yield. 
EXAMPLE 6 (Introduction of 7.alpha.-methoxy) 
(1) To a solution of 385 mg of diphenylmethyl 
7.beta.-(.alpha.-p-hydroxyphenyl-N-t-butoxycarbonylglycyl)amino-3-(1-methy 
l-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa- 
3-cephem-4-carboxylate in 6 ml of dihydropyran is added 3 to 4 drops of 
phosphoric acid in 4 to 5 portions. After about 1 hour, the mixture is 
diluted with ethyl acetate, washed with 5% aqueous sodium 
hydrogencarbonate solution and then aqueous sodium chloride solution, 
dried and evaporated under reduced pressure. The residue is stirred with 
petroleum ether. The obtained residue (520 mg) is chromatographed on 10 g 
of silica gel and eluted with benzene-ethyl acetate (5:1) to yield 373 mg 
of diphenylmethyl 
7.beta.-(.alpha.-p-tetrahydropyranyloxyphenyl-N-t-butoxycarbonylglycyl)ami 
no-3-(1-methyl-5-tetrahydropyranyloxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl) 
thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate. 
(2) To a solution of 282 mg of the product of above (1) in a mixture of 6 
ml of methylene chloride and 0.6 ml of methanol are added 50 .mu.l of 
t-butylhypochlorite and 0.6 ml of a solution (2 mmoles/ml) of lithium 
methoxide in methanol, and the mixture stirred at -55.degree. to 
-50.degree. C. for 25 minutes, cooled to -78.degree. C., mixed with 1 ml 
of dimethylsulfide and 0.5 ml of acetic acid, stirred for 15 minutes, and 
warmed to 0.degree. C. The reaction mixture is mixed with ethyl acetate, 
washed with 5% aqueous sodium hydrogen-carbonate solution and aqueous 
sodium chloride solution and evaporated under reduced pressure. The 
residue (307 mg) is dissolved in 15 ml of methanol, mixed with 1.5 ml of 
5% hydrochloric acid, allowed to stand at room temperature for 60 minutes, 
mixed with ethyl acetate, washed with 5% aqueous sodium hydrogen-carbonate 
solution and then aqueous sodium chloride solution, dried and evaporated. 
The residue (212 mg) is chromatographed on silica gel containing 10% water 
to yield 95 mg of diphenylmethyl 
7.beta.-(.alpha.-p-hydroxyphenyl-N-t-butoxycarbonylglycyl)amino-7.alpha.-m 
ethoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethy 
l-1-dethia-1-oxa-3-cephem-4-carboxylate as foamy material in 40% yield. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1790, 1710, 1690, 1595, 1495 cm.sup.-1. 
EXAMPLE 7 
To a solution of 2.903 g of p-nitrobenzyl 
7.alpha.-phenylacetamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxyl 
ate in 20 ml of dimethylformamide is added a solution of sodium 
1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-ylmercaptide 
(prepared from a suspension of 950 mg of the corresponding thiol in 
methanol by adding 30.9 ml of 0.193 M sodium methoxide and concentrating 
under reduced pressure) in dimethylformamide. After 30 minutes, the 
reaction mixture is diluted with methylene chloride, washed with 5% 
phosphoric acid and water, dried and evaporated under reduced pressure. 
The residue is chromatographed on silica gel and eluted with ethyl 
acetate-methylene chloride (1:1) to yield 1.80 g of p-nitrobenzyl 
7.beta.-phenylacetamido-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-tria 
zin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate. 
IR: .nu..sub.max.sup.KBr 1790, 1710, 1690, 1670, 1650, 1585, 1520 cm.sup.-1 
NMR: .delta..sup.CDCl 3.sup.+CD 3SOCD3 3.38s3H, 3.58s2H, 4.17s2H, 4.68s2H, 
5.20d (4 Hz)1H, 5.47s2H, 5.63dd(4; 9 Hz)1H, 7.2-8.4m9H, 8.77d(9 Hz)1H, 
12.6s1H. 
The starting material may be prepared from 3.262 g of p-nitrobenzyl 
7.beta.-phenylacetamido-3-acetoxymethyl-1-dethia-1-oxa-3-cephem-4-carboxyl 
ate on reaction with 2.25 g of boron chloride in 60 ml of methylene 
chloride at room temperature for 60 minutes in more than 93% yield. 
EXAMPLE 8 (Introduction of hydroxy-protecting group) 
(1) To a solution of 52 mg of diphenylmethyl 
7.beta.-phenylacetamido-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-tria 
zin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate in 1 ml of 
tetrahydrofuran is added 26 mg of isobornylchloroformate in the presence 
of 12 ml of N-methylmorpholine, and the mixture stirred for 40 minutes, 
diluted with ethyl acetate, washed with water, dried and evaporated under 
reduced pressure. The residue is chromatographed on 1.5 g of silica gel 
and eluted with benzene-ethyl acetate (3:1) to yield 36 mg of 
5-isobornyloxycarbonyloxy-6-oxotriazinyl compound in 54.3% yield. 
(2) The same starting material as (1) is treated with 2-equivalents of 
dimethyldichlorosilane and 4 equivalents of dimethylaniline to yield the 
corresponding silyl compound. 
(3) p-Nitrobenzyl 
7.beta.-phenylacetamido-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-tria 
zin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate (800 mg), 
N-methylmorpholine (200 mg) and 285 mg of isobornylchloroformate are 
dissolved in 25 ml of tetrahydrofuran and reacted at 0.degree. C. for 2 
hours. The reaction mixture is diluted with ethyl acetate, washed with 
water, dried and evaporated under reduced pressure. The residue is 
chromatographed on 35 g of silica gel and eluted with benzene-ethyl 
acetate (3:1) to yield 901 mg of the corresponding 
5-isobornyloxycarbonyloxy-6-oxotriazinyl compound. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 3430, 1795, 1760, 1720, 1685, 1610, 1515, 
1350 cm.sup.-1 
NMR: .delta..sup.CDCl.sbsp.3 0.8-2.1 ml6H, 3.32s3H, 3.60s2H, 4.18s2H, 
4.62s2H, 4.85t(6 Hz)1H, 5.00d(4 Hz)1H, 5.33ABq2H, 5.67dd(4; 9 Hz)1H, 
6.50d(9 Hz) 1H, 7.2-8.2m9H. 
(2) To a suspension of 62 mg of diphenylmethyl 
7.beta.-(.alpha.-p-hydroxyphenyl-N-t-butoxycarbonylglycyl)amino-3-(1-methy 
l-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa- 
3-cephem-4-carboxylate in 1 ml of dihydropyran is added 1 drop of 
phosphoric acid, and the mixture kept at room temperature for 50 minutes, 
diluted with ethyl acetate, washed with 5% aqueous sodium 
hydrogencarbonate and water, dried and evaporated. The residue is agitated 
in petroleum ether to yield 81 mg of diphenylmethyl 
7.beta.-(.alpha.-p-tetrahydropyranyloxyphenyl-N-t-butoxycarbonylglycyl)ami 
no-3-(1-methyl-5-tetrahydropyranyloxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl) 
thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylate. 
EXAMPLE 9 
A. Acylation of phenol 
(1) To a solution of 94 mg of diphenylmethyl 
7.beta.-(.alpha.-p-hydroxyphenyl-N-t-butoxycarbonylglycyl)amino-7.alpha.-m 
ethoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethy 
l-1-dethia-1-oxa-3-cephem-4-carboxylate in 2 ml of methylene chloride is 
added 0.5 ml of a solution of 6 .mu.l of N-methylmorpholine and 16 .mu.l 
of trichloroacetyl isocyanide in methylene chloride, and the mixture 
stirred for 30 minutes and pured into a mixture of ice water and ethyl 
acetate. The organic layer is separated, washed with water, dried and 
evaporated under reduced pressure. The residue is adsorbed on silica gel, 
and after 1 hour, slowly eluted with chloroform-methanol (98:2) mixture to 
yield 96 mg of diphenylmethyl 
7.beta.-(.alpha.-p-carbamoyloxyphenyl-N-t-butoxycarbonylglycyl)amino-7.alp 
ha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thio 
methyl-1-dethia-1-oxa-3-cephem-4-carboxylate in 72% yield. 
Rf=0.15 (TLC plate precoated by silica gel/chloroform:methanol (9:1)) 
(2) The following compounds are preparable in a similar manner to that 
mentioned in (1). 
__________________________________________________________________________ 
(RCH.sub.3) 
A E M COB 
__________________________________________________________________________ 
##STR96## .alpha.H 
H COOH or COOCHPh.sub.2 
2 
##STR97## .alpha.OCH.sub.3 
" COOH or COOCHPh.sub.2 
3 
##STR98## " " COOH or COOCHPh.sub.2 
4 
##STR99## " " COOH or COOCHPh.sub.2 
__________________________________________________________________________ 
B. Acylation of amino group 
(1) To a suspension of 97 mg of 
7.beta.-(.alpha.-p-hydroxyphenylglycyl)amino-7.alpha.-methoxy-3-(1-methyl- 
5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3- 
cephem-4-carboxylic acid trifluoroacetate in 2 ml of acetonitrile are added 
0.5 ml of propylene oxide and 0.25 ml of O,N-bistrimethylsilyacetamide, 
and the mixture stirred at room temperature for 10 minutes and mixed with 
45 mg of N-methylcarbamoyl chloride at 0.degree. C. The mixture is stirred 
for 1 hour, mixed with methanol and evaporated under reduced pressure. The 
residue is triturated in ether to yield 
7.eta.-[.alpha.-p-hydroxyphenyl-N-(N.sup.1,N.sup.3 
-dimethylureido)carbonylglycyl]amino-7.alpha.-methoxy-3-(1-methyl-5-hydrox 
y-6-oxo-1,6-dihydro-1,3,4-triazin-4-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4 
-carboxylic acid as powder in nearly quantitative yield. 
Rf=0.19 (TLC plate precoated by silica gel/acetic acid:ethyl acetate:water 
(1:5:1)) 
(2) To a suspension of 69 mg of 
7.beta.-(.alpha.-p-carbamoyloxyphenylglycyl)amino-7.alpha.-methoxy-3-(1-me 
thyl-5-hydroxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-o 
xa-3-cephem-4-carboxylic acid trifluoroacetate in 2 ml of acetonitrile are 
added 0.4 ml of propylene oxide and 0.2 ml of 
O,N-bis-trimethylsilylacetamide, and the mixture stirred at room 
temperature for 15 minutes, cooled with ice, and mixed with 41 mg of 
4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl chloride. The mixture is stirred 
for 40 minutes and evaporated under reduced pressure. The residue is 
agitated in petroleum ether, ether and ethyl acetate successively to yield 
62 mg of 
7.beta.-[.alpha.-p-carbamoyloxyphenyl-N-(4-ethyl-2,3-dioxopiperazin-1-yl)c 
arbonylglycyl]amino-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1,6-dihydr 
o-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid 
as colorless powder in 83% yield. 
Rf=0.33 (TLC plate precoated by silica gel/acetic acid: ethyl acetate:water 
(1:5:1)). 
The following compounds are preparable in a similar manner to that 
described in (1) and (2) immediately hereinabove. 
__________________________________________________________________________ 
(RCH.sub.3) 
A E M COB 
__________________________________________________________________________ 
##STR100## H H COOH 
2 " " " 
##STR101## 
3 " CH.sub.3 O 
" COOH 
4 
##STR102## H " " 
5 
##STR103## " " " 
6 
##STR104## " " COOCHPh.sub.2 
7 " CH.sub.3 O 
" " 
8 
##STR105## " " " 
__________________________________________________________________________ 
C. Cyclization of thiazole 
(1) To a solution of 132 mg of diphenylmethyl 
7.beta.-bromoacetoacetamido-7.alpha.-methoxy-3-(1-methyl-5-hydroxy-6-oxo-1 
,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxyl 
ate in a mixture of 1 ml of tetrahydrofuran and 1 ml of methanol is added a 
solution of 28 mg of thiourea and 23 mg of sodium hydrogen-carbonate in 
0.5 ml of water, and the mixture stirred at room temperature for 2 hours, 
poured into chloroform, washed with water, dried and evaporated under 
reduced pressure to yield 42 mg of diphenylmethyl 
7.beta.-(2-aminothiazol-4-yl)acetamido-7.alpha.-methoxy-3-(1-methyl-5-hydr 
oxy-6-oxo-1,6-dihydro-1,3,4-triazin-2-yl)thiomethyl-1-dethia-1-oxa-3-cephem 
-4-carboxylate as powder in 39% yield. 
Rf=0.30 (TLC plate precoated by silica gel/chloroform:methanol (10:1)) 
The following compounds may be prepared in a similar manner to that 
mentioned above. 
______________________________________ 
A E M COB 
______________________________________ 
##STR106## .alpha.H H COOCHPh.sub.2 
3 " " " COOH 
4 " .alpha.CH.sub.3 O 
" " 
______________________________________ 
PREATION 1 
##STR107## 
(a) To a suspension of 2.18 g of Compound 1 in 20 ml of chloroform is 
dropwise added a solution (9.5 ml; 17.5 mM) of chlorine in carbon 
tetrachloride at -20.degree. C. to -30.degree. C. with stirring. After 
about 30 minutes, the mixture gives a transparent yellow solution. This is 
washed with aqueous sodium hydrogen carbonate and saturated saline under 
ice cooling, dried over sodium sulfate, and evaporated to give Compound 2 
(2.49 g) as yellow product. 
NMR: .delta..sup.CDCl.sbsp.3 1.97s3H, 2.25sH, 3.47s2H, 4.89dd(1;7 Hz)1H, 
5.78d(1 Hz)1H, 6.55brd(7 Hz)1H, 6.83s1H, 7.2 ml 5H. 
(b) To a solution of 537 mg of Compound 2 in 3 ml of propargyl alcohol is 
added 500 mg of silver tetrafluoroborate at -23.degree. C. with stirring. 
After 1 hour, benzene and an aqueous sodium hydrogen carbonate are added 
thereto, and the mixture is stirred for a while and then filtered. The 
benzene layer is worked up in a conventional manner to yield Compound 3. 
(c) A solution of 1.0 g of Compound 3 in 10 ml of methanol is catalytically 
hydrogenated in hydrogen atmosphere with 0.25 g of 5% palladium-calcium 
carbonate catalyst. The product is worked up in a conventional manner to 
yield 0.88 g of Compound 4 in 88% yield. m.p. 110.degree.-112.degree. C. 
(d)-(1) Direct expoxidation. 
To a solution of 0.88 g of Compound 4 in 9 ml of chloroform is added 0.54 g 
of m-chloroperbenzoic acid and allowed to stand at room temperature 
overnight. The reaction mixture is washed with an aqueous hydrogen sulfite 
solution, an aqueous sodium hydrogencarbonate solution, and then water, 
dried, and concentrated. The residue is chromatographed on 20 parts by 
volume of silica gel and eluted with a mixture of benzene and ethyl 
acetate (4:1) to yield 475 mg of Compound 5 in 51.7% yield. 
(d)-(2) Via bromohydrin 
To a solution of 148 mg of Compound 4 in 2.0 ml of dimethyl sulfoxide and 
0.1 ml of water is added 60 mg of N-bromoacetamide under ice cooling, and 
the mixture is stirred at room temperature for 1.5 hours and then ice 
cooled. To this mixture is added 80 mg of potassium t-butoxide, and the 
mixture is stirred at the same temperature for 20 minutes, mixed with 
water, and extracted with ethyl acetate. The extract is worked up in a 
conventional manner to yield 120 mg of Compound 5. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 3410, 1775, 1720, 1680 cm.sup.-1 
m.p. 114.degree.-115.degree. C. 
PREATION 2 
##STR108## 
(a) To a solution of 7.31 g of Compound 1 in 100 ml of methylene chloride 
is introduced ozone for 20 minutes, and the resultant solution is stirred 
with 7.5 g of zinc powder and 100 ml of acetic acid at -78.degree. to 
0.degree. C. for 30 minutes. The solid is filtered off, and the filtrate 
diluted with methylene chloride, washed with water, dried and evaporated 
to yield Compound 2 as foam in quantitative yield. 
Rf=0.26, 0.17 (TLC plate precoated by silica gel/benzene:ethyl acetate 
(1:1)) 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1790, 1755, 1680 cm.sup.-1 
NMR: .delta..sup.CDCl.sbsp.3 3.56. 
The isomer at .alpha. position is isolated by chromatography on a column of 
silica gel. 
(i) Rf=0.26 (TLC plate precoated by silica gel/benzene:ethyl acetate (1:1)) 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1785, 1750, 1675 cm.sup.-1 
NMR: .delta..sup.CDCl.sbsp.3 3.57s2H, 3.63s2H, 4.85d(4 Hz)1H, 5.30dd(4; 9 
Hz)1H, 5.66s1H, 7.00s. 
(ii)Rf=0.17 (TLC plate precoated by silica gel/benzene:ethyl acetate (1:1)) 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1790, 1750, 1680 cm.sup.-1 
NMR: .delta..sup.CDCl.sbsp.3 3.58s4H, 5.53s1H, 6.97s. [the isomer] 
(b) To a solution of 5.07 g of Compound 2 in 80 ml of methanol are added 
1.82 ml of N-methylmorpholine and 1.28 ml of thionyl bromide, and the 
mixture stirred for 20 minutes and poured into a mixture of ice water and 
ethyl acetate. The ethyl acetate layer is separated, washed with water, 
dried and evaporated under reduced pressure. The residue (7.49 g) is 
dissolved in 80 ml of methylene chloride and mixed with 3.19 g of 
triphenylphosphine, and the mixture stirred at room temperature for 40 
minutes and poured into a mixture of ethyl acetate and ice water 
containing 5% sodium hydrogencarbonate. The ethyl acetate layer is 
separated, washed with water, dried and evaporated under reduced pressure. 
The residue (10.12 g) is chromatographed on 140 g of silica gel and eluted 
with benzene-ethyl acetate (1:1) to yield 7.06 g of Compound 4 as foam in 
71.5% yield. 
Rf=0.46 (benzene:ethyl acetate (1:2)); 0.20 (TLC plate precoated by silica 
gel/benzene:ethyl acetate (1:1)) 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1770, 1665, 1630 cm.sup.-1 
(c) To a solution of 8.79 g of Compound 4 in 200 ml of acetone is added 
Jones Reagent (2.5 mole/L), and the mixture stirred for 1 hour, mixed with 
a small amount of isopropanol, stirred for 15 minutes and filtered. The 
filtrate is mixed with ethyl acetate, washed with 5% aqueous sodium 
hydrogencarbonate and water, dried and evaporated under reduced pressure 
to yield 8.40 g of Compound 5 as foam in 95.8% yield. 
Rf=0.64 (TLC plate precoated by silica gel/benzene:ethyl acetate (1:2)) 
(d) To a solution of 8.30 g of Compound 5 in 120 ml of dimethylformamide is 
added a solution of sodium 
1-methyl-5-hydroxy-6-oxo-1,2-dihydro-1,3,4-triazin-2-ylmercaptide in 
dimethylformamide, prepared from a suspension of 1.56 g of the 
corresponding free mercaptan in methanol on addition of 49.4 ml of a 
solution (0.2 mole) of sodium methylate in methanol, and the mixture 
stirred for 40 minutes under ice-cooling, diluted with ethyl acetate, 
washed with water, 5% aqueous sodium hydrogencarbonate solution and then 
water successively, dried and evaporated under reduced pressure to yield 
8.58 g of Compound 6 as foam in 89.5% yield. 
Rf=0.30 (TLC plate precoated by silica gel/ethyl acetate) 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1775, 1710, 1690, 1670, 1620, 1595 
cm.sup.-1 
(e) A solution of 66.5 g of Compound 6 in 100 ml of dioxane is refluxed 
overnight under heating at 120.degree. C. in an oil bath and evaporated 
under reduced pressure. The residue is chromatographed on 150 g of silica 
gel and eluted with chloroform-methanol (200:1 to 50:1) to yield 3.0 g of 
Compound 7 as foam in 66.2% yield. 
Rf=0.35 (ethyl acetate); 0.17 (TLC plate precoated by silica 
gel/chloroform:methanol (95:5)) 
(f) To a solution of 3.23 g of Compound 7 in 30 ml of methylene chloride 
are added 2.55 ml of N,N-dimethylaniline and 1.51 ml of 
trimethylchlorosilane, and the mixture stirred at room temperature for 1 
hour, and mixed with 1.32 g of phosphorus pentachloride at -40.degree. C. 
The mixture is stirred for 1.5 hours, mixed with 12 ml of methanol at 
-60.degree. C., and then stirred at -60.degree. C. for 5 minutes and at 
0.degree. C. for 30 minutes. The reaction mixture is treated in a 
conventional manner to yield 2.38 g of Compound 8 as colorless foam in 
90.5% yield. 
Rf=0.08 (TLC plate precoated by silica gel/ethyl acetate) 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1795, 1715, 1690 (shoulder), 1585 
cm.sup.-1 
NMR: .delta..sup.CDCl 3.sup.+CD 3.sup.OD 3.31s3H, 4.04brs2H, 4.52brs2H, 
4.97d(4 Hz)1H. 
PREATION 3 
##STR109## 
(a) To a solution of 11.1 g of Compound 1 in 160 ml of methylene chloride 
is introduced ozone at -78.degree. C., and the resultant solution is 
stirred with 160 ml of acetic acid, 11.1 g of activated zinc powder and 
methylene chloride, until the temperature of the reaction mixture rises to 
0.degree. C., and filtered. The filtrate is washed with water, dried and 
evaporated under reduced pressure to yield 10.22 g of Compound 2 as 
colorless foam in 96.1% yield. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1775, 1750, 1685, 1495 cm.sup.-1 
(b) To a solution of 10.10 g of Compound 2 in 150 ml of methylene chloride 
are dropwise added 2.81 g of N-methylmorpholine and 2.15 ml of thionyl 
bromide under ice-cooling, and the mixture stirred for 20 minutes and 
poured into a mixture of ice water and ethyl acetate. The organic layer is 
separated, washed with aqueous sodium chloride solution containing 
hydrogen bromide, dried and evaporated under reduced pressure. The residue 
is dissolved in 150 ml of methylene chloride and mixed with 5.35 g of 
triphenyl phosphine, and the mixture stirred at room temperature for 1 
hour. The reaction mixture is washed with 5% aqueous sodium 
hydrogen-carbonate solution and aqueous sodium chloride solution, dried 
over magnesium sulfate and evaporated under reduced pressure. The residue 
is chromatographed on 30 parts by volume of silica gel and eluted with 
benzene-ethyl acetate (1:1) to yield 9.92 g of Compound 4 in 61.5% yield. 
(c) To a solution of 7.30 g of Compound 4 in 280 ml of acetone is added 
1.15 equivalents of Jones Reagent, and the mixture stirred for 50 minutes, 
mixed with isopropanol, stirred for 15 minutes and filtered. The filtrate 
is diluted with 400 ml of ethyl acetate, washed with 5% aqueous sodium 
hydrogencarbonate solution and aqueous sodium chloride solution dried over 
magnesium sulfate and evaporated to yield Compound 5, which is dissolved 
in 110 ml of dimethylformamide. To the solution is dropwise added a 
solution of 1 molar equivalent of sodium 
1-methyl-5-hydroxy-6-oxo-1,2-dihydro-1,3,4-triazin-2-ylmercaptide in 
dimethylformamide under ice-cooling. The reaction mixture is stirred at 
0.degree. C. for 1 hour and poured into a mixture of ice water and ethyl 
acetate. The organic layer is separated, washed with water, dried and 
evaporated under reduced pressure to yield 7.65 g of Compound 6. 
(d) A solution of 10.35 g of Compound 6 in 200 ml of dioxane is refluxed 
under heating for 6 hours and evaporated under reduced pressure. The 
residue is chromatographed on 250 g of silica gel to yield 3.85 g of 
Compound 7 in 52.7% yield. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1783, 1710, 1690, 1590 cm.sup.-1 
NMR: .delta..sup.CDCl.sbsp.3 3.35s3H, 3.50s3H, 3.70s2H, 4.05s2H, 4.53s2H, 
5.13s1H, 6.77s1H, 7.00s1H, 7.2-7.6 m, 11.03s1H. 
Rf=0.34 (TLC plate precoated by silica gel/ethyl acetate) 
(e) Compound 7 (1.34 g) is stirred in the presence of 1.52 ml of 
dimethylaniline and 0.60 ml of dimethylsilyl dichloride in methylene 
chloride for 60 minutes to yield the corresponding silyl compound, the 
latter is treated with 1.04 g of phosphorus pentachloride at -25.degree. 
C. to yield the corresponding iminochloride compound, and the latter 
stirred in 20 ml of methanol at 0.degree. C. for 40 minutes and mixed with 
2.6 ml of diethylamine. The mixture is stirred for 30 minutes, diluted 
with ethyl acetate, washed with water, dried and evaporated under reduced 
pressure. The residue is washed with petroleum ether and then ether to 
yield 0.98 g of Compound 8 as powder in 89% yield. 
IR: .nu..sub.max.sup.CHCl.sbsp.3 1790, 1720, 1710, 1690, 1595 cm.sup.-1 
NMR: .delta..sup.CDCl.sbsp.3 2.15brs2H, 3.32s3H, 3.50s3H, 4.03s2H, 4.53s2H, 
4.87s1H, 6.95s1H, 7.1-7.6 m 
Rf=0.21 (TLC plate precoated by silica gel/ethyl acetate) 
PHYSICAL DATA FOR EXAMPLES 
__________________________________________________________________________ 
##STR110## 
Rf value (TLC) 
Ar mp IR:.nu. .sub.max.sup.KBr (cm.sup.-1) 
(CH.sub.3 COOC.sub.2 H.sub.5 
:CH.sub.3 COOH:H.sub.2 O) 
__________________________________________________________________________ 
##STR111## powder 1782, 1710, 1680, 1585. 
0.28 (8:1:1) 
##STR112## " 1785, 1707, 1680, 1588. 
0.64 (3:1:1) 
__________________________________________________________________________ 
##STR113## 
Rf value (TLC) 
Ar mp IR:.nu. .sub.max.sup.CHCl.sbsp.3 (cm.sup.-1) 
NMR: .delta. (ppm) (CH.sub.3 COOC.sub.2 
H.sub.5) 
__________________________________________________________________________ 
##STR114## 
foam 1800, 1720, 1690, 1590. 
3.31s3H, 3.65s2H, 4.06bs2H, 4.46bs2H, 
5.02d(4Hz) 1H, 5.75dd(4;9Hz)1H, 7.00s15H. 
(CDCl.sub.3) 0.35 
##STR115## 
powder 3.23s3H, 3.40s2H, 4.07bs2H, 4.65bs2H, 
5.23d(4Hz) 1H, 5.67dd(4;9Hz)1H, 6.30s1H, 
6.88s1H, 6.97s1H, 7.27-7.77m10H. (d.sub.6 
DMSO) 
__________________________________________________________________________ 
##STR116## 
Rf value (TLC) 
Ar B mp IR: .nu. .sub.max.sup.KBr 
(CH.sub.3 COOC.sub.2 H.sub.5 
:CH.sub.3 COOH:H.sub.2 
__________________________________________________________________________ 
O) 
##STR117## H powder 1785, 1710, 1680, 1588. 
0.24 (8:1:1) 
##STR118## " " 1781, 1705, 1680, 1585. 
0.50 (3:1:1) 
##STR119## COOH " 1783, 1710, 1586. 
0.63 (3:1:1) 
##STR120## " " 1782, 1710, 1587. 
0.62 (3:1:1) 
##STR121## " " 1780, 1708, 1587, 1515. 
0.10 (5:1:1) 
##STR122## " " 1780, 1710, 1588, 1510. 
0.14 (5:1:1) 
##STR123## " " 3260, 1780, 1710, 1630, 1590, 
0.22 (5:1:1) 
__________________________________________________________________________ 
##STR124## 
IR: .nu. .sub.max.sup.CHCl.sbsp.3 
Rf value (TLC) 
Ar B mp (cm.sup.-1) 
NMR: .delta. (ppm) (solvent) 
__________________________________________________________________________ 
##STR125## H foam 1783, 1710, 1690, 1590. 
3.35s3H, 3.50s3H, 3.70s2H. 4.05s2H, 
4.53s2H, 5.13s1H, 6.77s1H, 7.00s1H, 
2.2-7.6m15H, 11.03s1H. 
0.34 (CH.sub.3 
COOC.sub.2 H.sub.5) 
1 
##STR126## " powder 3.25s3H, 3.52bs(3+2)H, 4.05bs2H, 
4.85bs2H, 5.07s1H, 6.27s1H, 6.97s1H, 
7.2-7.6m10H. (CDCl.sub.3) 
0.30 (CHCl.sub.3 : 
CH.sub.3 OH 
= 10:1) 
##STR127## 
##STR128## 
foam 1785, 1720, 1715, 1695, 1590. 
3.30s3H, 3.43s3H, 4.02bs2H, 4.42bs 2H, 
5.00s1H, (5.08+5.12)s1H, 6.97s 1H, 
7.00s1H, 7.1-7.9m23H, 10.85bs1H. 
(CDCl.sub.3) 0.47 (CH.sub.3 
COOC.sub.2 H.sub.5) 
3 
##STR129## 
##STR130## 
" 1785, 1720, 1712, 1690, 1590. 
3.30s3H, 3.48s3H, 3.75s3H, 3.80s3H, 
4.00bs2H, 4.45bs2H, 4.70s1H, 4.93s 2H, 
5.10s1H, 5.17s2H, 7.00s1H, 6.8- 7.6m22H, 
10.80bs1H. 0.47 (CH.sub.3 
COOC.sub.2 H.sub.5) 
##STR131## 
##STR132## 
" -- 3.30s3H, (3.43+3.47)s3H, 4.07bs2H, 
4.40bs2H, 4.73s1H, (5.07+5.10)s1H, 
7.00s1H, 6.7-7.6m24H. (CDCl.sub.3 
+CD.sub.3 OD) 0.50 (CH.sub.3 
COOC.sub.2 H.sub.5) 
##STR133## " " -- 3.28s3H, (3.47+ 3.50)s3H, 4.00bs2H, 
4.30bs2H, (4.78+4.81)s1H, 5.03s1H, 
6.90s1H, 6.97s1H, 7.0-7.6m24H. (CDCl.sub 
.3 + CD.sub.3 OD) 0.24 (CHCl.sub.3 : 
CH.sub.3 OH 
__________________________________________________________________________ 
=9.1) 
##STR134## 
Rf value (TLC) 
solvent system 
IR: .nu. .sub.max.sup.KBr (CH.sub.3 COOC.sub.2 
H.sub.5 : 
R A mp (cm.sup.-1) 
NMR: .delta..sup.CD.sbsp.3.sup.OD 
CH.sub.3 COOH:H.sub. 
2 O) 
__________________________________________________________________________ 
##STR135## powder 
1783, 1710, 1680, 1588, 1514. 
0.40 (5:1:1) 
NH.sub.2 CO 
" " 3445, 1785, 
1.21t(7Hz)3H, 3.43s3H, 3.67m4H, 
4.07q(7Hz)2H, 0.37 (5:1:1) 
1710, 1680 
4.20s2H, 4.53bs2H, 5.08d(4Hz)1H, 
5.60m(1+1)H, 
1590. (7.13+7.53)ABq(8Hz)4H. (CD.sub.3 OD) 
H 
##STR136## " 1781, 1735, 1705, 1671, 1592. 0.30 (5:1:1) 
" 
##STR137## " 1788, 1707, 1676, 1590. 
2.79s3H, 3.19s3H, 3.47s3H, 4.20bs2H, 
4.58bs2H, 5.41s1H, (6.75+7.34)ABq(8Hz)4H. 
(CD.sub.3 OD) 0.52 (5:1:1) 
" H " 1783, 1705, 0.40 (3:1:1) 
(CF.sub.3 COOH) 1680, 1590. 
H 
##STR138## " 1773, 1707, 1680, 1590, 1515. 
1.17t(7Hz)3H, 3.04bs3H, 3.50bs3H, 5.08s1H, 
.43s1H, (6.80+7.40)ABq(9Hz)4H (D.sub.2 
0.33 (5:1:1) 
NH.sub.2 CO 
" " 1782, 1709, 
1.21t(7Hz)3H, 3.43s3H, 3.53s3H, 
0.33 (5:1:1) 
1675, 1588. 
5.01s1H, 5.52s1H, (7.06+7.49)ABq(8Hz)4H 
(CDCl.sub.3 + CD.sub.3 OD) 
H 
##STR139## " 1772, 1707, 1680, 1590, 1515 
-- 0.39 (5:1:1) 
H 
##STR140## " 3360, 1780, 1710, 1680, 1590. 
2.80s3H, 3.23s3H, 3.50s3H, 3.53s3H, 
4.17bs2H, 4.43bs2H, 5.08s1H, 5.43s1H, 
(6.83+7.40) ABq(8Hz)4H. (CDCl.sub.3 + 
CD.sub.3 OD) 0.19 (5:1:1) 
H H " 1782, 1707, 
3.47bs6H, 4.17bs2H, 4.48bs2H, 
0.15 (5:1:1) 
(CF.sub.3 COOH) 1675, 1590, 
(6.87+7.47)ABq(8Hz)4H 
(CD.sub.3 OD) 
NH.sub.2 CO 
H " 1780, 1700, 
3.43s3H, 355s3H, 4.15bs2H, 4.47bs2H, 
5.11s1H, 0.34 (3:1:1) 
(CF.sub.3 COOH) 1675, 1588. 
5.17s1H, (7.20+7.61)ABq(8Hz)4H. 
(CD.sub.3 OD) 
__________________________________________________________________________ 
##STR141## 
Rf value (TLC) 
IR: .nu..sub.max solvent system 
Y R R' A mp (cm.sup.-1) 
NMR: .delta. (ppm) 
(CHCl.sub.3 : 
CH.sub.3 OH) 
__________________________________________________________________________ 
H H 
##STR142## 
##STR143## 1.20t(7Hz)3H, 3.40s3H, 3.60bs2H, 
3.90bs2H, 4.13bs2H, 4.53bs2H, 
5.02d(4Hz)1H, 5.33s1H, 5.43s2H, 
5.58d(4Hz)1H, (6.75+7.27ABq(8Hz)4H 
, (7.62+8.22)ABq(9Hz)4H. 
(CDCl.sub.3 + CD.sub.3 OD) 
0.19 (9:1) 
" " 
##STR144## 
##STR145## 
foam 1.43s9H, 3.37s3H, 4.10bs2H, 
4.48bs2H, 5.03d(4Hz)1H, 5.18bs1H, 
.67d(4Hz)1H, 6.80ABq(8Hz)2H, 
6.98s1H, 7.2-7.6m12H. 
OCH.sub.3 
" " " " 1790, 
1.40s9H, 3.35s3H, 
1710, 
3.55s3H, 4.03bs2H, 
1690, 
4.33b2H, 5.07s1H, 
1595, 
3.12bs1H, 
1495. 
6.77ABq(8Hz)2H, 6.95s1H, 
7.2-7.6m12H. 
(CDCl.sub.3 + CD.sub.3 OD) 
" NH.sub.2 CO 
" " " 1780, 
1.55s9H, 3.24s3H, 
0.15 (9:1) 
1735, 
3.54s3H, 3.96bs2H, 
1385. 
4.28bs2H, 5.01s1H, 
6.91s1H, 6.95ABq(8Hz)2H. 
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