JPS6056987A - Penem derivative - Google Patents

Abstract

NEW MATERIAL:A compound (salt) shown by the formula I [R1 is H, or hydroxy lower alkyl; R2 is carbamimidoyl lower alkyl, guanidino lower alkyl, or group shown by the formula II (Q1 is lower alkylene; Q2 is lower alkylene, or NH); R3 is H, or ester residue]. EXAMPLE:p-Nitrobenzyl( 5R,6S,8R )-2-ethylsulfinyl-6-( 1-hydroxyethyl)penem-3-carboxylate. USE:An antibacterial agent against Gram-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa. PREPARATION:For example, a penem derivative shown by the formula III (R4 is alkyl, aryl, or aralkyl) shown by the formula III is oxidized with an oxidizing agent in a solvent to give a sulfoxide derivative shown by the formula IV, which is reacted with a thiol compound shown by the formula R2-SH, and the protecting group is eliminated, to give a compound shown by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (I) [wherein R1 is a hydrogen atom or a hydroxy lower (in the formula, r
Qs represents a lower alkylene group) where Ql represents a lower alkylene group +Qt represents a lower alkylene group or -NK-).几represents a hydrogen atom or an ester residue] and pharmacologically acceptable salts thereof.

As used herein, the term "lower" refers to a straight or branched carbon chain having 1 to 6 carbon atoms, such as a methyl group as a lower alkyl group.

Ethyl group, deaf-purpyru group, isoptetravir group.

Examples include rubutyl group and isobutyl group.

Also, a methylene group is a lower alkylene group.

Examples include ethylene group, methylethylene group, loop tetrapyrene group, and the like.

Following penicillin and cephalosporin antibiotics, in recent years chenamycin (Japanese Patent Application Laid-Open No. 51-78191), P8-5
(JP-A-58-121702 and JP-A-54-8
Carbapenem antibiotics such as No. 0195) have been discovered from nature and have been reported to have strong antibacterial effects. On the other hand, penem compounds have been synthesized using these natural products as model compounds, and these carbapenems.

New β-lactam antibiotics such as Penem are physicochemically unstable, are subject to enzymatic degradation by dehydropeptidases, etc., and have many other unsatisfactory aspects as pharmaceuticals, so they have not been commercially available to date.

As a result of intensive research, the present researchers found that the general formula (I)
The new compound has strong antibacterial activity against Gram-negative bacteria including Durham-positive bacteria and Aeruginosa, and is also physicochemically and biochemically stable, making it useful as an antibacterial agent. They discovered this and completed the present invention.

In the general formula (1), suitable examples include lower alkyl groups having a hydrogen atom or a hydroxyl group, such as a methyl group, an ethyl group, a 1%-propyl group, an isoprivyl group, and a butyl group, and R1 is a substituent. Forms a lower alkyl group such as methyl, ethyl, ``propyl, isopropyl, decorated-butyl group, etc. having a carbamimidoyl group or guanidino group, or a 5- or 6-membered ring such as 2-iminopyrrolidine, 2-iminopiperidine, etc. or alicyclic guanidine substituents such as 2-amino-8,4,5,6-titrahydride tetrapyrimidine and 2-amino-1-imidacyline, and basic radicals are preferred. In addition, in the present invention, when an asymmetric carbon atom is present in the compound, stereoisomers occur. For example, if the asymmetric carbon atom is 1
In the case of IIL, two stereoisomers occur, so one is described as "isomer M" and the other as "isomer Bj" for convenience.In addition, IIL is a hydrogen atom, methyl, ethyl,
Isobutyl.

Straight chain or branched lower alkyl groups having 1 to 4 carbon atoms such as tert-butyl, lower alkoxy lower alkyl groups such as methoxymethyl and methoxyethyl, and lower aliphatic groups such as piva-oxymethyl group. Ester residues that also serve as protecting groups for group acyloxymethyl groups, 7-talidyl groups, or carboxyl groups during the synthesis of compounds of the present invention and can be easily removed under mild conditions include 1, for example, 0-nitrobenzyl, p-nitrobenzyl, and benzhydryl. Aralkyl or allyl groups such as groups.

Examples include trimethylsilyl group.

In general formula (1), the configuration of the carbon atom at position 5 is preferably the R configuration corresponding to natural penicillin, and suitable examples include a hydrogen atom and a 1-hydroxyethyl group. As a particularly preferred example, the configuration of the carbon atom at the 6th position to which the 1-hydroxyethyl group is bonded is the S configuration, and the configuration of the carbon atom at the 8th position to which the 1-hydroxyethyl group is substituted is R.
One example is the placement.

2-iminopyrrolidin-8-yl group as preferred R2,
2-iminopyrrolidin-4-yl group.

2-amino-8,4,5,6-tetrahydrobyrimidin-5-yl group, carbamimidoylethyl group.

A guanidinoethyl group is mentioned.

A suitable example is a hydrogen atom, and preferable examples of ester residues that can be metabolized include pivaloyloxymethyl group and phthalidyl group. Preferred ester residues include p-nitrobenzyl group, allyl group, and the like.

Note that some of the compounds of the present invention and intermediates may have tautomeric structures.

In this specification, it will be represented by one type of structural formula.

This is not meant to be limiting.

The pharmacologically acceptable salts include non-toxic carboxylic acid salts, such as metal salts such as sodium, potassium, aluminum, and magnesium, ammonium salts, and triethylamine, protylene, dibenzylamine, and penicillins;
Includes salts with non-toxic amines such as other amines used in salt formation of cephalosporins.

Particularly suitable salts include sodium salts and potassium salts.

Due to the presence of a basic group in the penem derivatives of the present invention, pharmaceutically acceptable acid addition salts such as mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.

Or acetic acid, citric acid, succinic acid, ascorbic acid,
Salts with organic acids such as methanesulfonic acid can also be used.

Particularly suitable salts include heptahydrochloride and sulfate. Furthermore, the compound of formula 1 may be in various solvated forms, and for example, hydrated forms are also included within the scope of the present invention.

The compound of the present invention can be formulated in a conventional manner using conventional pharmaceutical carriers, stabilizers, and excipients. Administration is by oral administration such as tablets, pills, capsules, and granules.
Rui is an intravenous or intramuscular injection.

Parenteral administration such as suppositories may be used.

The dosage is usually 25 (119 to 8,000 μl) per day for adults, which is divided into several doses, but can be increased or decreased as appropriate depending on age, gender, and symptoms.

The compound (1) of the present invention can be produced by the method exemplified by the reaction formula below.

1st step: Known method (J, An, Ohem, 8oc, 1
04°6188 (1982)) and the general formula θ) (wherein R,, R, are the same as above, and R4 is an organic group 5, such as an alkyl group).

A penem derivative represented by an aryl group such as phenyl or an aralkyl group such as benzyl or 7-enethyl is mixed with an oxidizing agent 1, such as perbenzoic acid, 9m-chlorofiltrate, etc., in a suitable solvent. , aromatic acid, hydrogen peroxide.

When oxidized with selenium dioxide, ozone or sodium metaperiodate, preferably with m-4-terbenzoic acid, a sulfoxide (...) is formed (in the formula, the wavy line at S→0 means a mixture of stereoisomers) is obtained in good yield. The sulfoxide obtained here is a mixture of stereoisomers, but can be suitably used in the next second step reaction without being separated. Reaction solvents used in this reaction include halogenated hydrocarbons such as dichloromethane, chlorotetraform, and carbon tetrachloride, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, water, acetic acid,
Pyridine, N,N-dimethylformamide (hereinafter referred to as D
MF), acetamide, dimethyl sulfoxide (abbreviated as MF), acetamide, dimethyl sulfoxide (
below.

Any solvent (including mixed solvents) that does not adversely affect the reaction raw materials and products, such as DM80 (abbreviated as DM80), can be suitably used. The reaction temperature is -50°C to 50°C, preferably -80°C.
Mild temperature conditions of 0° C. to room temperature are advantageous. A reaction time of 5 minutes to 4 hours (1 suitably 80 minutes to 1 hour is sufficient).

Second step; Sulfoxide compound (I) and thiol compound (2) obtained as described above. In the formula C, R3 is the same as above.

This is a substitution reaction with the general formula (representing a group different from R4 in VD), its acid addition salt, or its reactive derivative, and the solvent is DMP.

DM80. Tetrahydro-7rane (hereinafter abbreviated as THF),
Hexamethylphosphotriamide (hereinafter abbreviated as HMPA)
Any solvent (including mixed solvents) that does not adversely affect the reaction raw materials and products such as DMIF is suitable. The reaction temperature is usually -60℃ to room temperature, room temperature -80℃ to 0℃
is suitable. The reaction time is usually 15 minutes to 2 hours, especially 8
The thiol compound of general formula (2), which is preferably reacted for 0 minutes to 1 hour, is highly reactive when coexisting with a base, and the reaction progresses well, but it also proceeds without a base. Usable bases include alkylamines such as triethylamine and diisopropylethylamine, 1,8-diazabicyclo(6,4,0
)-7-undecene (hereinafter referred to as

DBU), alicyclic amines such as N-methylmorpholine, inorganic bases such as sodium hydroxide and potassium hydroxide,
Examples include metal alcoholades such as potassium t-butoxide and sodium methoxide, sodium amide, sodium hydride, diisopropylethylamine, D
BU is preferably used.

Examples of reactive derivatives of thiol compounds of the general formula (IO) include thiolate compounds represented by the general formula M8-R1 (in the formula, 1M is an alkali metal, and R1 is the same as above).In this substitution reaction, the general formula The thiol compound (my) is usually 1 to 8 equivalents of the sulfoxide compound (II), especially 1
It is preferable to use the base in an amount of 1.5 to 1.5 equivalents, and it is preferable to use the base in an amount equivalent to the amount of the thiol compound. However, if the thiol side) is an acid salt, good results can be obtained by further adding a base in an amount necessary to neutralize the added acid.

The substituted product produced in the above reaction is isolated by conventional post-treatment.

Eighth Step: If the above-mentioned substituted product has a protecting group, the protecting group can be further removed if desired. Examples of methods for deprotecting groups include hydrolysis using acids, bases, or enzymes, and reductive decomposition by hydrogenation.

The ester residue of general formula (I) is an aralkyl group such as p-nidodibenzyl group, benzyl group, benzhydryl group, t
-Butyl groups, silyl groups, etc. are hydrolyzed with acids such as formic acid and trifluoro-U acetic acid, p-nidodibenzyl groups, benzyl groups, benzhydryl groups, etc. are further treated with catalytic reduction using palladium carbon or platinum oxide, and methyl, In the case of an alkyl group such as an ethyl group, a compound in which R1 in general formula (1) is a hydrogen atom can be obtained by performing hydrolysis with a base.

Some of the substituted substances in the second step described above are difficult to isolate and purify depending on their physical properties.

When the purpose is to produce a compound in which R1 in general formula (1) is a hydrogen atom, better results can be obtained by removing the protecting group in the same reaction vessel without isolating the intermediate substituted product. It will be done. Especially when carrying out mass production, there is no need for complicated work.

It is a simple method with excellent yield and quality.

In order to produce esters that can be metabolized in the body, a compound of general formula (1) in which the stone is a hydrogen atom may be esterified in accordance with the method for penicillins and cephalosporins.

The penem derivative (I) of the present invention is a compound with excellent physicochemical stability, and is a compound of Durham-positive bacteria9, for example, 8. Aureus, 8m1th, 8. Evidermizois, 56
500, 8tr; Pyogenes.

G-86, 8tr, Mitis, IID 685.8tr.

E. faecalis, ATOO19488, etc. and L. coli, NIJJJ.

S, 7 Lexinelli 2a, 5508. Sal, Enteritide 4X, IID 604. H, Tk bay, ID97
8.0.7a4day TID 976 +Pr, Purgari X, 08601. Pr, Mirabilis.

IFO8849, ni, 2, - Moniet Typ@1゜1
ent, black crab * 0840B, Int, erotic lt'ness, ATOO8819, 8er, r4se, sense.

10100, Y, zuntepkorichika+ Te 591
It exhibits strong antibacterial activity and is useful as an antibacterial agent.

It is safely used as a medicine for humans and livestock, and can also be used for fish.

The compound of the present invention can also be used as a preservative for feed and as a disinfectant for medical equipment and the like.

Reference example 1: p −= ) 'o benzyl, (5B, 68.8B) −
2-ethylthio-6-(1-hydroxyethyl)penem-8-carboxylate (1) (8B,4R)-4-((ethylthio)thiocarbonylthio)-8-((R)-1-(1- Butyldimethyl-silyloxy)ethyl]-2-7zetidinone (88,4R)-(几-1-(t-butyldimethylsilyloxy)ethyl)-4-phenylsulfonyl-2-azetidinone (Tstrahedron Letters
, Vol. 22.5205 (1981)) 1.119°potassium ethyltrithiocarbonate 0.689. )' 0.16 g of JJI rubenzyl iodite is stirred at room temperature for 7 hours in a mixed solvent of JI Q ml and 80 ml of water. After separating the organic layer, washing with water, and drying, the solvent was distilled off under reduced pressure. The residue was subjected to column ximatography using 25 g of silica gel (benzene:
Purification with ethyl acetate (80°:l) gives the title compound as yellow crystals. Yield 9.5!9° Melting point 109~1
14℃.

IR(KBrd%sk) (sheet t-':l) 7
ONMRδ (ODOjs)” 0.08 (6H, @) 0.88 (9H, 5) 1-24 (8H-d -J-7Hz, OHs) 1-
87 (8H, t, J-7Hz.

-OHt -OHs) 8.24 (IH, m, 0s-H) 8-87 (2H, q, J-7Hz.

-0H1-OHs) 4.29 (IH, m, -0n-081) 5.68
(IH, d, J-8H1, 0, (It) 6, s 8
(IH, br, NH) F D l1lass m/e 865 (Calculated value for M elemental analysis 0+4HtyN0.8s8i 04
5.98. H7,44,N 8.8B Actual value 045
．． 95. H7,1? , N 8.76 (2) p-nito-tetrabenzyl g-((as.

4B) -4-((ethylthio)thiocarbonylthio)-
Compound Q obtained with 8-((6)-1-(t-butyldimethylsilyloxy)ethyl-2-oxo-1-azetidinyl]-2-oxo-acetate (1), 1969, Shiitubu tetrabillethylamine 0.689 was dissolved in 80-ethyl acetate, and p-nitosybenzyloxalyl chloride i, gsp was dissolved under water cooling.
and stirred at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with water, 5% sodium bicarbonate solution, and water, and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column filter using 20g of silica gel to remove the residue.
Purification by mudgraphy (benzene:ethyl acetate-50:1) gives the title compound as a yellow oil. Yield 1
．． 809゜IR(neat)cm-': 1805.1750.170O NMRδ -0,09(6H,s, 5t(OHs)z)0,
'I 5 (9H1s, OHa) 1-15 (8
H, d, J-7Hz, 0Hs) L28 (8H, t
, J-'IHz.

CH, -OH,) 8.81 (2H, q, J-7Hz.

OHa -0Hs) 8.50 (IH, dd, J-5Hz.

4 Hz, O, -H) 4-1 to 4-8 (L H, m * 0H-081) 5
．． 80 (2H,s, Ar-0 几)6-65 (I
HldlJ-4Hz, 04-H) 7.45 (2H, d
, J-9Hz, Ar-H)8.17 (2H,d,
J-9Hz, ArJI) (8) p-nidodibenzyl
(5R,6s,8R)-2-ethylthio-6-(it
-Butyldimethylsilyloxyethyl)penem-8-carboxylate (2) Compound L289 was dissolved in 200we of benzene, and 148g of triethyl phosphite was added to 8.5g of the mixture under reflux.
It takes time to drip. Reflux for another 8.5 hours, and after cooling, add water, 0.5N hydrochloric acid, water, and 5% hydrogen carbonate to the reaction solution.
Wash with water and then water. After drying with anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure. The residue is purified by columnar tetramathography using silica gel 709 (benzene:acetic acid ester-60:1) to obtain the title compound as a pale yellow oil. Yield 0.689°IR (neat) cm-': 17'80.1685NM
Rδ(0DOj,)? 0-04 (8H+s) 0.06 (8H,5) 0-'I8 (9H,s) 1.26 (8H,d, J-7Hz, OHs) 1.8
8 (8H, t, J-7Hz, OH!0H8) 2.99
(gH, dq, J-7Hz.

OH, ωh) 8.72 (IH, dd, J-4Hz, 2Hz.

06-H) 4J 5 (IH, m, 0s-H) 5.80 (2H, ABq, J-14Hz.

Ar-0ut-) 5.64 (IH, d= J"2Hz+0s-H)7.
60 (2H, d, J-9Hz, Ar-H) 8.20
(2H, d, J-9Hz, Ar-H) υνλmax
(Dioxane): 842.262nm FD Mass: m/e 524 (M”) (4)
p-Nitrobenzyl (5B, 6s.

8R)-2-Ethylthio-6-(1-hydroxyethyl)penem-8-carboxylate (8) The obtained compound "85q + Vinegar #811!
7 Q A mixture of 1.68 m of a 11M tetra-butylammonium fluoride solution of tetrahydro-7 run and 10-ml of tetrahydro-7 run was stirred at room temperature for 40 hours. The reaction solution was diluted with ethyl acetate, washed successively with water, a 5% aqueous sodium bicarbonate solution, and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals are washed with ether to give the title compound as pale yellow crystals.

Yield 204m9° Melting point 166-167°C.

IR(l03rdisk)am-' :8400
．． 1770, 1780°'1675 NMRδ (ODolm): 1.86 (8H, d, J-7Hz, OHa)1.
87 (8H, t, J-7Hz.

OH, CH8) 2.99 (2H, dq, J-7I (z, 2Hz.

CMl, JJH3) 8.78 (IH, dd, J-7Hz, 2Hz.

oa-n) 445 (IH, quintet, J -7Hz.

0, -H) 5.88 (2H, ABq, J-14Hz.

Al-0Ht) 5.66 (LH=d, J-2Hz, 0s-H
)7.60 (2H, d, J=9'Hz, Ar-H)8
．． 20 (gn, d, J-9Hz, Ar-H)υνλm
axc dioxane) nI11=1!168. 842 Elemental analysis Calculated value for 0syH+5NtOJt 0
49.74. H44B, N 6.88 actual value 04
9.99. H4,66, N 6.6+1 Reference example'2 = 5-mercapto-2-p-nitrobenzyloxylponyliminohexahydropyrimidine HS(N-C00pNB (1) 2-(N-t-butoxycarbonyl amino)-1
-p-Methoxybenzylthio-1-cyanoethane α-chlorogastric acrylonitrile 7g was added to dioxane 80-
4.5% of 29% aqueous ammonia was gradually added dropwise, and the mixture was stirred at room temperature for 20 minutes. 2-t-butyloxycarbonyloxyimino-2-phenylacetonitrile 209 was added to the reaction solution, stirred at room temperature for 6 hours, and further heated at 80° C. for 24 hours. After evaporating the solvent under reduced pressure, the residue was extracted with chloroform, and the organic layer was dissolved in water, 10% hydrochloric acid, and saturated hydrogen carbonate).
Wash sequentially with IJum water and saturated saline, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residual liquid was stirred with carbon tetrachloride, insoluble matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 150 g of benzene, 6.1 g of p-methoxybenzyl mercaptan and 9.6 g of DBU were added, and the mixture was stirred for 18 hours. The reaction solution was diluted with ethyl acetate, washed successively with 2.5N hydrochloric acid, saturated sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, column chromatography using 100 g of silica gel (
Purification with benzene:ethyl acetate (5:l) gives the title compound as a pale yellow oil. Yield 8.89°NMRδ(O
D(Mm)' 1.48 (9H,It, 0(OHs)s)8-2
~8.6 (8Hrm + CI-aCr■t)
8,'l 6 (8H,ll, -00HI)8.89
(2H,s, -0Ht-Ar)4, 9-5.2
(I H, m, -Nu)6.82 (2H, d, J-9
Hz, Ar-H) 7.28 (2H, d, J-9Hz
, Ar-1 () (2) 8.1 g of sodium borohydride was added to 1-amiz-8-(N-t-butoxycarbonylamino)-2-p-methoxybenzylthiobium tetrapanetrahydro 7rane 100-. Added 9g of trifluoroacetic acid
Gradually drip. Compound 5 obtained in (1) is added to the above reaction solution.
, 2g of tetrahydrofuran 20-solution was added and the mixture was heated at room temperature.
．． Stir for 5 hours. excess sodium borohydride.

Water was gradually added to decompose, diluted with further water, extracted with chloroform, and the organic layer was washed with saturated saline and dried over magnesium sulfate.

The solvent is distilled off under reduced pressure for 7 hours to obtain the title compound as a pale yellow oil. Yield 6.2P.

NMRδ(ODOjm)' 1-40 (9H,s, 0(OHs)s)8.0
~8-6 (5H+m+o,-a,.

0s-H, 0s-Hz) 8.7ri and 8.80 (5H, each810H
, O-1'-OH-containing-k) 6.80 and 1.28 (each i9H, d.

J = 9Hz, Ar-H) 8.2-8.7 (2H, Ill, -Nu-) (8)
1.8-diamino-2-(p-methoxybenzylthio)
Compound 5.29 obtained with propane (2) and trifluoro vinegar 50d
Add anisole 8- and let it cool on ice for 80 minutes, then at room temperature for 80 minutes.
Stir for a minute. After concentrating the reaction solution under reduced pressure, water was added to the residue to dissolve it.

Wash with benzene, make the aqueous layer alkaline with concentrated ammonia water, and extract with Ritaroform. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain the title compound as a colorless viscous oil. Yield 2. ．． 99°NMRδ(
OD (M,): L, SO (4H, br, s, -NHffi) L8~
8.0 (5H,m+ O+-Hz +ax -H,O
,-H! ) 8, 65 (fA H,s, -0Ht-Ar)8-
72 (8H9s, 0HsO-)6.78 (2H
, d, J-9Hz, Ar-H)? -19(2Hld +
J-9I (z, Ar-H) (4) Compound 1.19 obtained with 5-p-methoxybenzylthio-2-p-nitrobenzyloxycarbonyliminohexahydropyrimidine (8) was dissolved in tetrahydrofuran 16
- dissolved in p-nitrobenzyl N-(methoxy(methylthio)methylene]carbame) (J, Ohem,
8oc, Perkin I +2644 (1978
1.49 (synthesized using p-nitrobenzyloxycarbonyl chloride instead of ethyl chlorov formate) was added according to the method described in 1.), and the mixture was stirred at room temperature for 16 hours. The precipitated insoluble matter is collected by filtration to obtain the title compound as a colorless powder. Convergence fi1.11°NMRδ (ODOIm)
: L6~B-5(5H9m, -GHt■-9-8-OH
-) 8.64 (2H,s, -OH,-8)L8 (8
H,! l, OH, O') 5.10 (gH, dew, -0000H! -) 6.8
1 and 7.15 (each 2H, d.

J = 9 Hzv Mr-E) 7.50 and 8.16 (each 2H, d.

J -9Hz, mr-H) 8.4-9.0 (2H, br, -NH-) (5) 5
-Mercapto-2-p-Nitrobenzyloxycarbonyliminohexahydropyrimidine (4) To 480 m9 of the compound obtained, anisole 1- and trifluoroacetic acid 5- were added, and 0.1 m of trifluoromethanesulfonic acid was added under ice-cooling at the same temperature. After stirring for 115 minutes, the mixture was concentrated to dryness under reduced pressure.

The residue was subjected to column chromatography on 18 g of silica gel (
Purification with chloroform:methanol (50:1) gives the title compound as a candy. Yield: 8551141°NMRδ (CD(M,)? 1.88 (IH, d, J=8Hz, -8H)8.
4-8.55 (8H, m, -8-OH-.

-〇a -H, -(Is -H) 8.6~8.95 (2H,m, -0s-H--O@
-H) 5.82 (2H,s, -0000Ht -)7.
56 and 8.17 (each 2H, d.

JmGHz, Ar-H 9,55 (2H, br, s, -NIl-) Reference Example 8
: 2-Imino-8-mercaptopyrrolidine trifluoromethanesulfonate (1) a-p-methoxybenzylthiopyrrolidine-2-
Dissolve 8 g of sodium hydroxide in 100% of water and add 4
18.75 F of -amino-2-chlorobutyric acid and 17.29 F of p-methoxybenzyl mercaptan were then dissolved and stirred at room temperature for 24 hours. Wash the reaction solution with benzene.

The aqueous layer was acidified with acetic acid while cooling, and the precipitated crystals were collected by filtration, washed with water and acetone, and dried to form colorless crystals of 4-amino-
2-Methoxybenzylthiobutyric acid21. F9 is obtained.

Melting point 200 Nj!　05℃.

5.1 g of this product was heated and stirred in an oil bath at 200 to 205° C. for 15 minutes to obtain a candy-like substance.

This is purified by column chromatography on Silicage/I/159 (chloroform, ethyl acetate) and recrystallized from silylform-isopropylether to obtain the title compound as colorless crystals. Yield 4.18 F.

Melting point: 106-107°C.

IR (KBr disk) Cff1-': 16
90.167O NMRδ(opajs): 1.7~1B-fJ (IH,me 04-H)fA
-2~2.6 (I H, m, 0n-H) @, l
~8. @ (3H, m, 0.-H.

and 0. -H) 8.78 (8H,s,0OHs)8.95 (j
lH, A11q, J-18Hz.

8-OH Goose-Ar) 6-47 (IH*m 1 book) 6.82 and 7.80 (each 2H, d.

J -81Hz, Ar-H) (2) 2-Ethoxy-8-p-methoxybenzylthio-1-viroline epichlorohydrin 1.48F, Bontrifluoride F ether complex (BF, .]!It, O)
8g, Me@rwe i synthesized from ether 20-
Dissolve n reagent (BF401 b-) in dichloromethane 80-, 8-p-methoxybenzylthiovireridine-2
-on 8.88 g was added, and the mixture was stirred for 2 hours at room temperature for zO minutes. Add a solution of 8 parts potassium carbonate and 60 parts water under water cooling.
Insoluble matter is filtered off, the organic layer is washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residual solution is purified with a column of silica gel 809 (benzene:ethyl acetate-1=s) to give the title compound as a colorless oil. Yield Ll
6g.

IR(neat)cWI-': 164 ONM δ
(OD(M, ): 1.86 (8H,t, J-7Hz.

-〇Horse-0Hs) 1-7~L1 (IH9m, 04-H)LX~B-8
(I H9m, 04-H) 8-4~4.0 (5H+
me 0s-Hz +0, -H and -8-0Ht
-Ar)8-79 (IsH,s, 0011m
)4.1&4 (2H1q+ J-7Hz 1oii
t-(](,) 6.82 (211, d, J-8Hz, Ar-H)I
J 8 (BH, d, J-8Hz, Ar-H) (8)z
-Imino-8-(p-methoxybenzylthio)bisilidine 810 ml of 2-ethoxy-8-p-methoxybenzylthio-1-viroline and 69 q of ammonium chloride are dissolved in 20 ml of methanol and heated under reflux for 15 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in water and washed twice with ethyl acetate. The aqueous layer is made alkaline with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The precipitated crystals are washed with isopropyl ether to obtain the title compound. ° Yield 160 Is9 ° Melting point 89-90 °C.

IR (KBr disk) em-': 1665HM
Rδ (0DC7s) j l, 8 ~ L6 (gn, m, 0.-H,) 8-4 ~
L 7 (8Hz m + a, -u, and 0, -H) 71.68 (gHls, BOHx)8,'l
6 (8H,s, 0OHs)4.88 (2H,
br, s, NH)6.80 (2H, d, J-9H
z, Ar-H) Fu-20 (2H, d, J-9Hz, A
r-H) Elemental analysis (%) Calculated value for O+tH+5NtO8 061.0? , H6,1l12. N 1
1.84 Actual value 060.87. H6, 71, N 1
1.74(4) 2-Imino-8-mercaptopyrrolidine trifluoromethanesulfonate 2-imino-8-p-methoxybenzylthiobiUlysine 2861119 and anisole 540■ are dissolved in 1.5 mt of trifluoroacetic acid and stirred. Add trifluoromethanesulfonic acid (20 drops) at room temperature, and stir at the same temperature for 45 minutes. The reaction solution was concentrated under reduced pressure, and the residue was washed with whole petroleum ether and then with isopropyl ether to obtain the title compound as a brown powder. Yield 260■.

NMRδ(D*0)' 2.0~L4 (I Hlm, 04-H) 2.6~
8.0 (IH, m, 04-H) a, s ~4-0
(2Hz m+ a, -n, )4.27 (IH, d
d, J-8 Hz and 7 Hz HOs -H) Example 1 (1) p-2) obenziAz (5R,68,8R)
-2-ethylsulfinyl-6-(1-hydroxyethyl)benem-8-carboxylatesenitrobenzyl (SR,68,8R)-2-ethylthio-6-(1-hydroxyethyl)penem-8-carboxylate) 185q was dissolved in dichloromethane 80°C and m-chloroperbenzoic acid 110°C was dissolved at -80°C to -20°C.
Add M and stir at the same temperature for 80 minutes.

Furthermore, 40 μm of m-chloroperbenzoic acid was added and stirred at the same temperature for 15 minutes. The reaction solution was diluted with dichloromethane, washed twice with 5% aqueous sodium bicarbonate and then with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residual liquid is purified by column chromatography (benzene:ethyl acetate-1=2) using silica gel 12W to obtain the title compound as a colorless oil. Yield: 95■.

IR(neat)am-': 1 Bo, 1
685HMRδ(0DOjs)' 1.87 (21H, d, J-ITlz, 0He)
1.40 (8H,t, J-7Hz.

OH*OHs) 15.08 (IH, q, J-7Hz.

OH, OH,) 8-11 (IH, q, J=7Hz.

OH, -OH,) 8-8~4.0 (IHlm, 0s-H) 4.28
(LH, dq, J-7Hz, O, -H) I5-85 (
2H, ABq, J = 14. Hz.

Ar-0Ht) 5.75 (0.5H, d, J-2Hz.

0eJI) 5.87 (0.5H, d, J-2Hz.

Os-H) 7.59 (LH, d, J-9Hz, Ar-H) 7.6
1 (LH, d, J = 9Hz, Ar-H) 8.24
(2H, d, J-9Hz, At-H)υν λmax
(dioxane) nm: 851 (2) (t+R, 68,
8R)-6-(1-hydroxyethyl)-2-Cfl-
p-Nitrobenzyloxycarbonyliminohexahydropyrimidin-5-ylthio]Penemu 8-carboxylic acid The compound iaowg obtained from p-nitrobenzyl ester (1) was dissolved in a mixed solvent of tetrahydrogen-acetonitrile (1:1) lO - dissolved in
5-Mercapto-2-p-nide p-benzyloxy-ruponylimii-hexahydride i-pyrimidine 14 (119) was added to the solution of the above mixed solvent 8, and heated at -40°C under an argon atmosphere.
The above mixed solvent 1- of DEU70■ was cooled to ~-50 tl.
Add solution.

After 80 minutes, further 5-methyb)-4-p-ditopenzyloxyluponylimide/hexahyde νpyrimidine 50
119. and DBU2fitmti are dissolved in the mixed solvent as described above, added, and stirred at the same temperature for 1 hour. The mixture is diluted with ethyl acetate, and the precipitated insoluble matter is collected by filtration, washed with ethyl acetate, and dried to obtain the title compound 184■ as a yellow powder.

The mother liquor was further purified by preparative thin layer chromatography (developed with 5:1 form:methanol) to obtain the title compound 20. Yield 204++19° Melting point 1r) 8-1
68℃.

IR (KBr disk) cm-': 1770.
1680. 1600 (sh) NMRδ(0DOla DR(80do) '1.84
(8H, d, J-'IHz, -0Hs) 8.25
~8.9 (6H,m,5-OH<.

-0Ht-NH-,0s-H) 4.0 to 4.25 (IH,m, -0H-OH)5-N
6 (2H+s, -0Ht-Ar)5.8
? (2H, ABq, J-14Hz.

-OHt-A r ) 5-72 (IB, d, J-19Hz, ca-H)7.
4-7.8.8.1-8.35 (8H, m, Ar-H) Mass: m/e 659 (M 勺(8) (5R,68,8B) -2-(2-Amino-
Compound 24119 obtained with 8,4,5,6-tetrahydrobyrimidin-5-ylthio)-6-(1-hydroxyethyl)penem-8-carboxylic acid (2) was diluted with tetrahydryl7ran4.
Dissolve in 0-16M phosphate buffer (pH 7.0), add 5 ooq of platinum acetate, and perform catalytic reduction under 4 atmospheres of hydrogen at room temperature for 1 hour. The catalyst was removed by filtration, the filtrate was concentrated, the remaining aqueous solution was washed twice with dichloroform, the aqueous layer was concentrated, and the residue was purified with Diaion Up-G.

Purify by column chromatography (1.8 cm x 1 gcm). Excluding the 7 lactyone that flows out with water,
Collect and concentrate the 5% tetrahydro-7-lactone eluted with water. The concentrated solution was again subjected to high performance liquid chromatography (HPLO) (carrier: Microbondervac C18).
, Solvent: 10% acetonitrile-water, flow rate i 4 d
/min), and the 7-lactone containing the target compound is collected and lyophilized to obtain the title compound as a colorless powder. Yield 86 capes.

υν λmax (HtO)n"' 259.81!! (ε-5290) IR (KBr dlsk ) cm-' : 1 7 7
5HMRδ(nto): 1-4 (8H1d, J-8J(z, -CjHs)
8.4-8-8 (4H,m, -0Ht-Nu)8
．． 9 (IH, m, -8-OH-) 4.05 (IH, dd, J=8Ez.

2 Hz, -On -H) 4.86 (LH,m, -0H(OH)-)5-80
(IH9d, J-2H, -05-H) HPLO retention time 25 minutes Example 2 (5R,68,8R)-6-(1-hydroxyethyl)
4-(2-iminopyrrolidin-8-ylthio)penem-
p-Nidotetrabenzyl 8-carboxylate (liR, 68,8L)-2-ethylsulfinyl-'6-(1-hydroxyethyl)penem-8-carboxylate 90m9. j! ! -Imino-3-mercaptopyrrolidine trifluorotetramethanesulfone 0 salt 789 is dissolved in dimethylformamide 1.11+-, diisopropylethylamine 85I119 is added while cooling to -40°C, and the mixture is stirred at the same temperature for 20 minutes. The reaction solution was diluted with a mixture of 16v of Tetrahuman Tetsuran and 0.1M phosphate buffer (pH 6,0) 1G-, and platinum oxide 9.
Catalytic reduction is carried out at room temperature for 1 hour under 4 atmospheres of hydrogen in the presence of 0w#g. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the organic solvent was distilled off. The concentrated solution was washed 5 times with chloroform, the aqueous layer was concentrated under reduced pressure, and the concentrated solution was washed with Diaion HP-20 (L8
Purify by column chromatography (cm x 17 cmK). Excluding the part eluted with 260% water, concentrate the eluted part with 5% tetrahydro 7 run and water, and reconcentrate the concentrated solution using high performance liquid columnarography (PLO) (carrier: Microbonderpa, C16, solvent: 5% acetonitrile-water,
A flow rate of 8.65 d/min) was applied to collect the 7-lactone containing the desired product and lyophilization gave the title compound as a colorless powder.

Yield 18q.

IR(KBr disk)e+a-':1770
．． 1700.1590 uv 1Htx (Hz0)nm': 255.82
5 NMR δ (pto): 1.219 (8H9d, J-7Hz, 0Hs)2.
2-g, o (IH+ ITlt pyrrolidine 04-H) 2.6-8.2 (IH, In, pyrrolidine 0, -H) 8.7-4-0 (2H, m, pyrrolidine 0, -H,) 4.04 (11Et, dd, J-7Hz, 2H
2°o, -a) 4.8 S (IH, m, Cm-H) 5.80 (IH, d, J-2Hz) HPLO retention time: 12.4 min and 18.2 min Example 8 (5R ,68,8B)-6-(1-hydroxyethyl)
-2-CB-iminopyrrolidin-4-yl-thio)penem-8-carboxylic acid (isomer A and isomer B) using 2-imino-4-mercaptobitetradine p-toluenesulfonate 80μ The reaction and post-treatment were carried out in the same manner as in Example 2 to obtain the title compound.

Isomer A: Yield 12m9 IR (KBr disk ) es+-': 1fufu 0
, 169O NMR δ (neo): 1.40 (8H, d, J-7Hz, O horse) L9-8.
9 (8H,m, -8-OK- and -0R1-0-
NH) 4.01 (IH, dd, J-7Hz and 2Hz+ O@-H) 4.1~4.5 (8HI m, O, -H and -H)
R1-Nu-0-N) 4.80 (ROD) 5.80 (IH, d, J-mHz, 0s(I)υ
ν 1~gw(HtO)am: 256.8a8 HPLO retention time 14.8 min [Carrier i Nucleosll 701+1 (101
1111X 800Htx) Solvent; Acetonitrile:
Water-1: 1.9° flow rate; 3. (Ij/n1ln) Isomer B: Yield Fu Misaki I R (KBr disk) cm-'': l flo5,1
695 NMRδ(D*O): 1-86 (8H1d, J-7Hz, G11m
)! ! , 9-8.8 (8H, m, -8-0) L- and -au, -a-NI () 4.00 (IH, dd, J = 'IHz and 2H
z, 0. -H) 4-1 to 4.5 (8H+m*Os-H and -OH*-NfX-C-N) 4.80 (HOD) 5.76 (IH, d, J-ffiuz.

-■) uv 1Htx(H,O)s*: 254, 824
HPLO retention time? 16.1 minutes (Conditions for high-speed liquid separation: same as above) -8-carboxylic acid J, Org, GIhem, :4JJ-1486(1
Using 2-carbamimidoylethyl mercaptan 48sp synthesized by the method of 968), the reaction was carried out in the same manner as in Example 2 and post-treated to obtain the title compound. Yield 27■.

IR (KBr disk) cm-': 1760.
1685 NMRδ(nto): 1.88 (8H, d, J-7Hz, 0Hs)2.
8-8.2 (Q H, m, -8-OH*-0Ht-)8
．． 2~Lf (QH,m, -B-OH2-4,00(I
H, dd, J-7Hz, mHz.

06-H) 4.88 (IH, quintet, J-7Hz.

0, -H) 4.80 (HOD) 5.76 (IH, d, J-2Hz.

0, -H) υν λmax (HIO)3m: 258 + 8
22HPLO retention time: 9.2 minutes Example 5 (IsR,68,8B)-6-(1-hydroxyethyl)-51-(guanidinoethyl-1-thio)penem-8
- using 2-guanidinoethyl mercaptan carboxylate.

The reaction and post-treatment were carried out in the same manner as in Example 2 to obtain the title compound as a colorless powder.

IR (KB r disk ) cm-1:8876
．． 1760.1650(sh)l62O NMRδ1tol L85 (8H, d, J-6Hz, OR,)2.
95~B-5 (2H1m, 80TIt) 8, 61! (
2H,t, J-6Hz, Q(tNH)8.97
(I H, dd, J -6Hz, 2Hz.

0, -H) 4.2-4-4 (I H, m, 0a-H) 5-7
5 (I H+ d, J-2Hz, 0s-H) υν
λmax (HIO) s*: 259, 881 HPLO retention time: 10.6 minutes

Claims (2)

[Claims] (1) General formula [wherein, Rf means a hydrogen atom or a hydroxy lower alkyl group, Rt means a carbamimide alkylene group, Qt
means a lower alkylene group or -NH-), and R1 means a hydrogen atom or an ester residue] or its tautomer, and penem derivatives and salts thereof. (2) (SR, 6B) A compound according to claim 1, which is a penem derivative.A compound according to claim 1.A compound according to claim 1.9 A compound according to claim 2 or 8.