JPS5984885A - 5-(r)-trans-6-substituted carbapenem compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R1 is alkyl or hydroxyalkyl; R2 is the group of formula II [n is 1-3; X is lower alkyl, amino or substituted amino; Y is OH, OR3 (R3 is alkyl, aralkyl or aromatic group), SR3, amino or substituted amino]} wherein the steric configuration of C-5 site is (R) and its salt. EXAMPLE:(5R,6S)-3-( 2-S-Carbamoylpropylthio)-6-(1-hydroxyethyl)-1-azabicyclo[3,2, 0]hept-2-en-7-one-2-carboxylic acid. USE:Remedy for infectious diseases. Effective to Gram-positive and Gram-negative bacteria. PROCESS:The compound of formula I can be prepared from an optically active beta-(S)-aminoglutaric acid monomethyl ester via the compound of formula III (R is H or protecting group) and the compound of formula IV.

Description

Detailed Description of the Invention The present invention is based on the general formula (1), where X is a lower alkyl group, an amino group, or a substituted amino group, and Y
is an optically active sulfur-containing residue represented by 0H10IL, (R3 is an alkyl group, an aralkyl group, an aromatic group), 8"3 (R3 is an alkyl group, an aromatic group, an amino group or a substituted amino group) The steric configuration at the U-5 position represented by Carbapenem antibiotics differ from conventional penicillin and cephalometric β-tuctum antibiotics in that they have a unique basic structure and have strong antibacterial activity against both Durum-positive and Guhum-negative bacteria. In addition to chenamycin, oripanoic acid,
Several new carbapenem antibiotics, such as P8-5 and carbetimycin, have been discovered by fermentation methods. However, since the amount of these products produced is small and unstable, attempts have been made to easily produce 1M derivatives that are stable and have excellent antibacterial activity using total synthesis or semi-synthesis methods. ing.

In the conventional stereochemistry of these carbapenem compounds, the configuration of the carbon atoms at the o-5 and 0-6 positions of the carbapenem skeleton in the formula is considered to be important for the expression of antibacterial activity. Especially O-
It is preferable that the steric configuration at the 5-position is (targeted). Methods for synthesizing carbapenem compounds in which the steric configurations at the c-5 and O-6 positions are defined include: (1) optical resolution of the racemate; 2) fermentation. However, method 1) has the drawback of using an expensive resolving agent and going through a multi-stage separation process, and method 2) is a method for producing carbapenems by fermentation of the basic compound. Compounds have additional points for large-IA accumulation. In addition to these methods, a method for obtaining a carbapenem compound with the configuration at the c-5 position (IQ) using optically active L-aspartic acid as a starting material has been published (Japanese Patent Laid-Open No. 55-27169, 1977
-142213). However, with this method, the number of carbon atoms is reduced to 1
It is necessary to elongate the film, which requires a multi-step process.

The present inventors defined the configuration at the c-5 position of the carbapenem compound as (B), and further determined the R configuration at the c-6 position.

As a result of repeated research to develop a new and unique manufacturing method in which the substituent is defined as 6-α for the β-lactam ring,
By using optically active β-(8)-aminoglutarate monomethyl ester as a starting material for synthesizing the optically active carno(benem) compound of the present invention, the configuration of the c-5 and c-6 positions of the carbapenem compound can be improved. The present invention was completed by discovering that it is possible to easily define the formula (1).
where R+ +R2 (as defined above) is a novel carbapenem derivative.

The present inventors introduced an optically active sulfur-containing organic compound into the side chain at the c-B position of the compound in the formula, and the substituent It1 at the C-6 position was 6-α relative to the β-octum ring. The present invention was completed by discovering that a 95-(IM-) lance-6-substituted carbapenem derivative bound by coordination is chemically stable and has excellent antibacterial activity.

As 5-(1<l-trans-6-fii converted carbapenem compounds, chenamycin and PS-5, which were discovered in nature, are already known as compounds with excellent antibacterial activity, but as in the present invention, , 5-(E)-)lansu'6-substituted carbapenem compounds having an optically active sulfur-containing substituent at the O-8 position are novel compounds.

To specifically illustrate the novel 5-(IQ-) lance-6-substituted carbapenem compound I of the present invention, the bonding form of R1 substituted at the c-6 position is 6-α to the β-fuctam ring, Examples of I include a methyl group, an ethyl group, a hydroxyethyl group, and a l-methy/L/t-hydroxyethyl group.The R2 group substituted at the e-B position is an optically active sulfur-containing substituent. , is bonded to carbon at the C-8 position with a thiol group.Specifically, it is a substituent consisting of optically active sulfur-containing amino acids such as cysteine and homocystine, and their derivatives.As derivatives of these sulfur-containing amino acids, the amino group and carboxyl group substituents. Examples of amino group substituents include N-ho7remyl group, N-acyl M (N-acetyl group, N-benzoyl group, etc.), N71''/'muimyl
Examples include an N-carbamoyl group represented by 'i/L', -N-C-NZ (Zker(, 1), or an N-thiocarbamoy 1'v group represented by -N-C-NZ1).

Examples of substituents for carboxyl groups include ester groups (methyl ester, ethyl ester, benzyl ester, etc.),
Compounds in which 8 of a thioester group (-0-8Of13, 1 sulfur amino acid and derivatives) is oxidized can also be used as the substituent hole 2. Also, as R2, a substituent consisting of an optically active sulfur-containing carboxylic acid and its derivatives can be mentioned.

Specifically, optically active -80H2-CH-000H1U
I(.

-S -C)l-CEIz-000)1. %, and these substituted with a hydroxyl group. Examples of these carboxyl group substitutes include ester groups (methyl ester, ethyl ester, benzyl ester, etc.) and O000. Further, compounds in which 8 of the above optically active sulfur-containing carboxylic acids and derivatives are oxidized can also be applied as the substituent.

The 5-(homogeneous trans-6-substituted carbapenem compound of the present invention has a wide range of antibacterial properties against Gram-positive bacteria and Gram-negative bacteria, as shown in Table 1), and has a wide range of antibacterial properties for the treatment of bacterial infections. It is useful in the treatment of respiratory infections, urinary tract infections, gastrointestinal diseases, intestinal infections, and tatori.

(> Josen Muneshiro) The method of synthesizing the optically active carbapenem compound described above by the present inventors uses (4S)-4-substituted- 2
-Azetidinone compound is stereospecifically obtained, and optically active trans-3-substituted-4-(carpoxymethyl-2-
This is a method of obtaining an azetidinone compound and then deriving it into a carbapenem ring. The synthesis of this important intermediate (4 in Reaction Scheme I below) is an optically active β-(Eil-aminogluta/
1/acid monomethyl ester and further (4S)-
A feature of the method of the present invention is that it can be easily carried out by stereospecifically alkylating a 4-substituted-2-azetidinone compound (3 or 6 in Reaction Scheme I).

That is, the method of the present invention involves subjecting optically active β-(S)-aminoglutarate monomethyl ester to a ring-closing reaction to produce 4-(8) in producing a 5-(l)ranno-6-substituted carbapenem compound and its salt. -Methoxy-carbonylmethifre-2-fuzetidinone was obtained, and trans-3-substituted-4-(radical-carboxymethyl-2-azetidinone derivative 4 υ group, hydroxyalkyl 5-(IQ-) lance-6, characterized in that the group 几 obtains ■ (or represents a protecting group)
- A method for producing a substituted carbapenem compound and a salt thereof.

The above-mentioned important intermediate compound can be produced by a stereospecifically simplified method, so that 5-(I<1-)
-Substituted cal/<benem compounds can be produced industrially more advantageously than before.

(hereinafter referred to as "Fusaku [phase])" (S)-β-aminoglutarate monomethyl ester (1) was prepared by the method of Ohno and the present inventors using dimethyl β-aminoglutarate. It can be easily obtained by enzymatic hydrolysis of Esthe/L/derivatives.
7-182891). The conversion of compound 1 to 2 was carried out using a redox-based condensation reagent developed by Ohno et al. It can be obtained in good yield (Japanese Patent Publication No. 57-77670)
).

4-(S)-methoxycarbonylmethyl-2 of compound 2
There are two routes from -azetidinone to the important intermediate Compound 4, and route A is faster by 1 m. That is, Compound 2 is hydrolyzed in a solvent such as methanol, ethanol, or tetrahydrofuran in the presence of an alkali such as sodium hydroxide or potassium hydroxide at -10 to 80°C for 0.5 to 4 hours, and then further hydrolyzed with dimethylformamide and acetonitrile. silylating agent in a solvent such as μ, -10 to 80°0,
The compound is reacted between 0.5 and 101'F& in the presence of a base such as triethylamine or diisopropylethylamine. Examples of the silylating agent include t-butyldimethylchlorosilane, t-butyldiphenylchlorosilane, and triphenylchlorosilane, among which t-butyldimethylchlorosilane is most preferred.

Alkylation reaction 8 → 4 is carried out in a solution of tetrahydrofuran, dimethoxyethane, diethyl ether, etc. from -100 to
8 is reacted with a strong base such as lithium diisopropylamide, lithium hexamethyldisiwodide, potassium hydride or the like in an amount of twice the equivalent at -10"C to form erulate,
Then, by adding a sufficient amount to a 10-fold excess of acetaldehyde, acetone, aliphatic aldehyde such as methyl iodide, ethyl iodide, ketone, or alkyl halide, the pores 1 become 1-hydroxyethyl, l- Compound 4, which is a methyl group, ethyl W, etc. to methyl-1-hydroxyethyl, can be obtained. At this time, the steric configuration at the C-4 position in compound 4 maintains the optical activity of the starting compound and assumes a (ladder) steric configuration.On the other hand, compound 4
1 (,1 of the substituent at position 08 is α-lactam ring,
The configuration i″f of the type i″f is preferentially taken by the alkylation conditions of the process of the invention.1 In addition to this route, route B can also be used to convert the target 4-methoxycarbonylmethy)L/-2-azetidinone into tetrahydrofuran. , in a solvent such as dimexane, diethyl ether, etc., with a minor agent such as sodium borohydride, lithium borohydride, etc., at 20°C to solvent reflux temperature, 2 to IO
of compound 5 (homogeneous 4-hydroxyethyl-
Reduce to 2-azetidinone. 5 was then treated with a silylating agent in a solvent such as dimethylformamide or acetonitrile.
10 to 80"C, 0,5 to 10 hours, react in the presence of a base such as triethylamine or diisopropylethylamine, and convert the amide proton of β-octam and the hydroxyl group of the side chain to a silyl group, preferably a t-butyldimethylsilyl group. Protect and convert to compound 6.

Then, by a reaction similar to the alkylation reaction in A)), J is 1-hydroxyethyl, i-mer-
Compound 7, which is a 1-hydroxy]nityl, methyl, and ethyl group, is removed. In this case, the configuration of the carbon at the 4-position of compound 8 in the alkylation according to the method of the present invention is (Ic), and the bond of the If substituent R at the 8-position is α-type with respect to the β-lactam ring.Next, 8 in a solvent such as methanol, ethanol, acetone, tetrahydrofuran, etc. in the presence of hydrochloric acid, sulfuric acid, etc.
10 to 20"C, react for 5 to 2 hours to regenerate the 4-position hydroxyethyl group to obtain compound 8. Oxidation reaction 8
→For 4, react 8 with pyridinium dichromate in dimethylformamide at 10-50'C for 2-10 hours, or react with Joanne's reagent or choline in acetone.
'React with the reagent at 0-80° for 2-8 hours to obtain Keiyo Chugoku Compound 4.

Conversion of Compound 4 to various carbapenem compounds can be carried out according to the above formula (see Tetrahedron Letters, 278B (1980)).
, reacted with N-carponyldiidazole to form an imidazolide, and treated with Mp salt of malonic acid monoester,
Side chains can be elongated.

The protective group hole is removed, the diazo compound is made with toluenesulfonyl azide, etc., and this is converted into a diazo compound using rhodium (It) acetate catalyst.
Ka Q! The door was then closed to obtain two Fl-ketoesters.

Keto ester contains optically active amino acids and optically active compounds.
1; Cocarboxylic acids or their derivatives (R'S■
) and then catalytic conversion in the presence of Baladia mucarpolymer, etc., to obtain the desired novel optically active carbapenem compound (1).

Isolation of the carbapenem compound synthesized as described above is carried out using the reaction mixing power after catalytic reduction.
-20 etc. resin f1], desalted, and made into resin 2@
The desired powder can be obtained by drying. At this time, the target product can also be isolated as a sodium salt or potassium salt.

In the 5-(IC-) lance-6-substituted carbapenem compound in the method of the present invention, when the substituted M at the C-6 position is 1-hydroxyethyl, an asymmetric carbon is also present in -hydroxyethyl. Therefore, when compound 3 or 6 is algylated with acetaldehyde as described above, a racemate is formed at the C-8 position. 5-(U-
) lance-6-substituted carno(benem compounds are derived from this c-
The racemic form at position B is also included, but the optically active form of this is 8-(1<l, 5-(, L9-
) Lance-6-hi.

Droxyethylcarbapenem compounds can also be prepared using the following method V.

Compound 3-pronged 1r'! (48) 4-g<” of compound 6
-2-Azetidino/(N-acetylimidazole was added to the compound in the presence of lithium diisopropylamide at -10
l-Hydrofluoride was prepared by reaction in a tetrahydrofuran solvent at 0 to -10°C to 7-cetylate the 8-position of the β-fukucum ring, followed by stereoselective reduction with monoselectlide in ether. Compound 4' can be obtained with the steric configuration of the diethyl group (reaction formula ■). From compound 4°, a carbapenem skeleton is formed by the method described in reaction formula ■, and the steric configuration at the 0-8 positions is I!!Ii'!The 5-(no-trans-6-hydroxybenem compound) can be obtained.

(J Kushita Yoiro) (-0 or more optically active (81-β-aminoglutarate monomethyl): [With ster as the base, trans-8-substituted-4-(1? According to the method of the present invention, 2-azetidinone can be easily synthesized in one culm, and a new cal/<benem compound can be synthesized in one culm via this intermediate. It becomes possible.

Examples T of the present invention will be listed below and specifically explained.

(Jbunsen 0) Example 1 (5几, 68)-8-(2-8-carbamoylpropylthio)-6-(1-hydroxyethyl)-1-azabicyclo(8,2,0)hept- 2-en-7-one-2
-Carboxylic acid step 1 Synthesis of 4(几)-(2-hydroxyethyl)-2-azetidinone 4 (8)-Methoxycarbonylmethyl-2-azetidinone (1) a, oy to dry tetrahydrofuran 60
Add lithium borohydride while stirring.
Add 75f in portions. After the addition, stirring was continued for 2 hours while heating to 70°C, and then acetic acid-methanol (5
+/-8ml> Add the mixed solution to stop the reaction. The reaction solution was concentrated to dryness and subjected to silica gel column chromatography (
benzene-acetone=1:1) to obtain white crystals of 2. Get Of.

Step 2 4αL)-(2-(0-dimethyl-t-butylsilyl)
-Hydroxyethyl)-1N-dimethyl-t-butylsilyl-2-azededinone ~ 8 Compound 2 (4
, 28F) in N,N-dimethylformamide 100
While cooling it on ice and stirring, add 8.2 f of triethylamine,
Add 12.2 g of dimethyl-t-butylsilyl chloride all at once. After stirring for 80 minutes, the mixture was gradually warmed to room temperature and stirred for a further 8 hours.

After the reaction, the salt is filtered off, the solvent is distilled off, ether-water is added, and the ether layer is washed with hydrochloric acid and saturated saline, and then dried and concentrated to obtain a pale yellow oil 11.84F of Compound 8.

Step 8 (88,4R)-8-(1-hydroxyethyl)-4-
(2-(0-dimethyl-t-butylsilyl)-hydroxyethyl) -1-N-dimethyl-t-butylsilyl-
Synthesis of 2-Azetidinone - To 20 td of dry tetrahydrofuran at 78 DEG C. are added 2.3 y of diisopropylamine and 18.4 ml of n-butyllithium (1,6 M hexane solution). The solution is stirred at -78° C. for 80 minutes and then compound 3 (6, Of) dissolved in 15*t of tetrahydrofuran is added. After stirring at -78°C for 40 minutes, 4 ttrl of acetaldehyde was added at once, and the mixture was further stirred at -78°C for 30 minutes.
Stir for 0.2 molar phosphate buffer (pH 6, 8).
) Add 70 vrl to terminate the reaction. Vinegar (β-ethyl) was added to this mixture, extracted, washed with water, dried, and the solvent was removed. , yielding compound 6.091 of 4a.

Step 4 (8S, 411) 8 (IT'-nitropenzyloxycarbonyloxyethyl)-4-(2-(0-dimethyl-t-butylsilyl)-hydroxyethyl)-1
Synthesis of -N-dimethyl-t-butyllithium-2-azedinone 120*t of anhydrous tetrahydrofuran in which Compound 4a (6,7f) was dissolved was cooled to -78°C, and 120*t of n-butyllithium (1,6M hexane solution) was added. * Add t slowly. After stirring at −78°C for 15 minutes, p-
Nitrobenzyl 1-xycarbonyl chloride (4.1 F) was added to water (water and tetrahydrofuran) over 5 minutes. Stirred for 2 to 8 hours at the same temperature, and added with 0.2 mol of phosphate buffer ( pH 6, 8) is added to stop the reaction. Ethyl acetate is added to extract, washed with water, and dried.
7 tons of luene = 20:1) to obtain 8.71 tons of oily substance 4b.

Step 5 (88.4 liters) -8-(1-p-dil-lobenzyloxycarbonylmexyethyl)-4-(2-hydroxyethyl)-1-N-dimethyl-t-butylsilyl-2-azetidinone Synthetic compound 4b (7.2g) was dissolved in 250ml of methanol, and 50rrl of 0.5N hydrochloric acid was added while stirring while cooling with water.
Continue stirring at the same temperature for 2 hours. After confirming the completion of the reaction with 'L'LO, add potassium hydrogen carbonate powder to neutralize the pH, and concentrate the methanol layer under reduced pressure.The remaining liquid is extracted with ethyl acetate, washed with saturated brine, dried, and concentrated. After drying, silica gel column chromatography (toluene-acetone = 1
When treated with 0:1), the oily compound 5 is converted into 4. 9
9 Get.

Step 6 Synthesis of (as. 4n.)-a-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-(carboxymethyl)-1-N-dimethyl-t-butylsilyl-2-azetidinone Compound 5 (4 Add 18 ml of 6N Jones reagent in several portions to 350 πl of the acetone solution of .5y) under ice-cooling and stirring. After continuing stirring at the same temperature until no change was observed on TLO, isopropyl alcohol was added.
Squash the excess oxidizing agent, add sufficient pressure of ethyl acetate, and use Celite to filter out insoluble matter. The p solution is washed with saturated saline, dried, and concentrated to obtain 8.8f of oily substance 6.

Step 7 (88.4 liters) -8-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-(8-P-nitrobenzyloxycarbonyl-2-oxopropyl)-1-N
-Synthesis of dimethyl-t-butylsilyl-2-azetidinone NB PNB Ni On2 Sheet NO2 Mono- of malosic acid in 10 ytt of dry tetrahydrofuran
p-nitrobenzyl ester 7,58 fl and magnesium methoxide i. 4iy was added and stirred at room temperature for 4 to 5 hours until a homogeneous solution was obtained, and the solvent was distilled off.
Magnesium, get around. Next, compound 6 (8, 511)
of dry tetrahydrofuran solution 1B0r/1.1'
- After adding 1.66 f of carbonyldiimixol at room temperature and stirring at the same temperature for 2 hours, 8.2 f of the above magnesium salt was added.
160 g of a solution of dry tetrahydrofuran in which 100 g was dissolved was added to one portion, and the mixture was further stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform) to obtain Compound 7 (4.2y).

Step 8 (3G,411Ll-8-(1-p-dil-lovenzylcarbonyldioxyethyl)'-4-(8-p-
Synthesis of nitrobenzyloxycarbonyl-2-oxopropyl)-2-azetidinone Compound 7 (4.0 g) was dissolved in 200 gt of methanol, and 8 hours of concentrated hydrochloric acid was added while stirring while cooling with water, and the mixture was stirred at the same temperature for 8 hours. After adding a sufficient amount of ethyl acetate and washing with saturated brine, the organic layer was dried, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform-acetone = 10:1).
) to obtain compound 8 (8,7y).

Step 9 (88,4L)-8-(1°-p-nitrobenzyloxycarbonyl"xyethyl)-4-(B-, p-nitrobenzyloxycarbonyl-2-oxo-8-diazopropyl)-2- Synthesis of Azetidinone Compound 8 (1,,7
0g) and p-toluenesulfonyl azide 0. '15f
1.1 of triethylamine while stirring and cooling with water.
Add 0f. The mixture was stirred at the same temperature for 80 minutes. The mixture was further stirred at room temperature for 1 hour to complete the reaction. After the reaction, the resulting salt was separated, washed with ethyl acetate, and concentrated under reduced pressure together with the P solution.
The residue was subjected to silica gel column chromatography (chloroform:acetone-1021) to obtain compound 9 (
1,42f) is obtained.

Step 10 (511,6s)-p-nitrobenzyl-6-(1-p
-nitropenzyloxycarbonyloxyethyl)-1
- Synthesis of butane-3,7-sion-2-carboxylate to azabicyclo(8,2,0) Compound 9 (1,82F) and rhodium (...) acetate 10119 were added to 800+l of dry benzene, and the suspension was Heat under a stream of air and reflux for 1 hour.

After cooling, the insoluble matter is separated and the furnace liquid is concentrated, and Compound 10, which forms one large white foam, is used.

Step 11 Synthesis of 2-(S)-rubamoylpropanediol 3-
Acedelthio-2-(S)-methyl-fropionic acid chloride 11 (11) is dissolved in 5 g of dry methylene chloride, and 50 m/37% aqueous ammonia is added while stirring under water cooling. After stirring for 10 minutes, the precipitate was collected and combined with the methylene chloride layer and concentrated to dryness to obtain a white solid of compound 12 (70%).
Get 5 points.

NM几(90Mf(z, 0DOIB) δ:
1.25(d, 3.Ff, J=-G!ON Part 2
) Step 12 (5]L,68)-p-nitropencyl-8-(2-
Synthetic compound of 8-carbamoylpropylthio)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo[8,2,O':lhept-2-en-7-one-2-carboxylate 10 (800IV) with 70t of acetonitrile
Dissolved in 4-dimethylaminopyridine 2 under water cooling.
'/q%N,N-diisopropylethylamine 0.8m
1 of diphenyl phosphoryl chloride was added and stirred for 10 minutes, and then 0.8 g of diphenyl phosphoryl chloride was added and stirred at the same temperature for 1 hour. Then N
, N-diisopropylethylamine 1.6 ml and 2
-(S)-rubamoylpropanethiol 12 (400
Add 10 l of acetonitrile solution of rg) and leave to stand in the refrigerator overnight. A sufficient amount of ethyl acetate is added to this, and after washing with saturated brine, the organic layer is dried and concentrated under reduced pressure.

This was purified by silica gel column chromatography (benzene-acetone = 5:1) to obtain pale yellow powder 690 of Compound 18.

Step 18 (5R,68)-8-(2-8-carbamoylpropylthio)-6-(1-hydroxyethyl)-1-azabicyclo(8,2°0)hela 1--2-en-fuone-2
- Synthesis of carboxylic acid Compound 1B (600) and 10%
Palladium-carbon catalyst 500 ~ 20ml dioxane and 10wt 0.1M phosphate buffer (pH 7.0)
Add to the mixed solution of (e) and hydrogenate in an autoclave at a hydrogen gas pressure of 4"J/att2 for 8 hours. The catalyst was separated from P and washed with water. The P solution was combined with the P solution, and then extracted with ethyl acetate.
Apply 20 ml of the resulting aqueous layer to a Diaion 1 (P20 column, wash with water, and elute with water-acetone system. For each fraction, the fractions with maximum absorption in the ultraviolet region of 800 nm at 5 are collected and frozen. Compound 14 (8101y) is obtained by drying.

1.28~1.84 (m, BI engineering, -0IL-OH
8), 2.78-8.80 (m.

5II, 0-4f1.0-6H, -8-OH2-0-
), 4.08-4.48(m, 2H,O-5,I
-IO(4-OH8)IR(KEr)Cm-' 175
0,1680.1600,1400UV a, x
800 n, m Example 2 (1,68)-'3-(2-8-ruboxib-pyrthio)-6-(1-hydroxyethyl)-1-azabicyclo(8,2°0]hept-2 -en-7-one-2-
Carphonic acid step 1 Synthesis of 2-(S)-(p-nitrobemethyloxycarbonyl)propanethiol 8 2-8-carboxypropanethiol 19C2,41)
is tritylated in methylene chloride by adding triethylamine and trityl chloride to give 8-tridelthio-2-8-methyl-propionic acid 16(10,41) in the form of a syrup. Next, 16 was dissolved in N,N-dimethylformamide, triethylamine and p-nitrobenzyl bromide were added, and the mixture was stirred at room temperature. The solvent was removed and silica gel column chromatography was performed to obtain a syrup-like 8-tridelthio-
2-8-Methyl-propionic acid-p-nitrobenzyl ester 17 (6,8811 is obtained.
2g) was dissolved in acetone, silver nitrate dissolved in a mixture of pyridine and methanol was added and stirred, and the precipitated solid was scraped off to obtain silver salt 1°82f. This is suspended in a mixture of chloroform and ether, concentrated hydrochloric acid is added, the mixture is stirred at room temperature, water is added, and the mixture is extracted with chloroform. Wash the organic layer with water,
After drying and concentrating, a pale yellow solid of 2-8-(p-nitrobenzyloxycarbonyl)propanethiol 18 was obtained.
Get 0q.

Step 2 (5R,68)-1)-nitrosamethyl-8(2-8-
(p-nitrobenzyloxycarbonyl)-propylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,2,O)hept-2-en-7-one-carboxy Using 2-(8)-(p-nitrobemethyl suboxycarbonyl)propanethiol in place of 2-(S)-carbamoylpropa>thiol in Step 612 of Example 1,
The same operation as in step 12 of Example 1 was carried out to prepare compound 19 (870+1+Z).

Step 8 (5R,68) -8(2-8-carboxylpropylthio)-6-(1-hydroxyethyl)-1-azabicyclo(8,2゜0]hept-2-en-7-one- 2-
Synthesis of carboxylic acid Similarly to step 18 of Example 1, heptacompound 1
9 (700F19) was catalytically reduced using a 10% palladium-Kumu carbon catalyst, and the same post-treatment procedure yielded compound 280q of 20.

1.80-1.80 (m, 8H, -0, [0HB),
2.80-8.85 (m.

5H, 0-4H, 0-6H, -8-OH2-0), 8
．． 90-4.50 (m, 2.H, 05,H, HOOH
OHB)1I also (KBr)C71+-' 1760
．． 1610.1400 Water UVλmax 29672m Example 8 (51L, 68)-8-(8-2-amino-2-carboxyedyldi)-6-(1-hydroxyethyl)-1
-azabicyclo(8,2,O)hept-2-ene-7-
Synthesis of 2-(S)-))-nitrobemethyloxylponylamino-8-mercaptopropionic acid p-nitrobenzyl ester Synthesis of cysteine hydrochloride 21 (3,1Of) After tritylation 22 in the same manner as Step 1 of 2, p-21-1-1-
Lopenzyl formate is reacted with p-nitrobenzyl in MF to introduce a protecting group into the amino acid (23), and react with p-nitrobenzyl in MF to form 24. Trityl 8 was removed from 24 in the same manner as in the previous step, and 2-(S)-p-
Nitrobenzyloxycarbonylamino-8-mercaptopropionic acid p-nitrobenzyl ester 25 (1
, 7f).

Step 2 (5R,68)-p-nitrobenzyl-8-((S)-
2-p-nitrobenzyloxycarbonyl-2-p-nitrobenzyloxycarbonylaminoethylthio)-6
-(1-p-nitrobenzyloxycarbonyloxyeral)-1-azabicyclo(8,2,O)hept-2
-Synthesis of -en-7-one-carboxylate" In step 12 of Example 1, 2-(S)-p-nitrobenzyloxycarbonylamino-8-mercaptopropion instead of 2-(8)-carbamoylpropanethiol The same procedure as in step 12 of Example 1 was carried out except that acid p-nitrobenzyl ester was used to obtain 760 g of a pale yellow solid of compound 26.

Step 8 (5 liters, 68)-8-(S-2-amino-2-carpoxyedylthio)-6-(1-hydroxyethyl)-1-
Azabicyclo(8,2,0)hept-2-en-7-one-2-carboxylic acid Compound 26 (500Tl1f) was catalytically reduced in the same manner as in step 18 of Example 1, and compound 27 (
97M//).

NMR (90MHz, D20) δ: 1.80-1.
84 (m, 8h.

OH0nB), 2.80-8.88(m, 5H,0
4H, 0-6H.

80H20'), 4.00-4.52 (m, 2)
1.05)1. I(OOI(ORB)-IR(KBr):l-' 1760,1590.14
05UV "!'ax 802 nyn Example 4 (5B, 68>-8-<2-8-carbamoylpropylthio)-6-(1-hydroxy-1-methylethyl)-
1-Azabicyclo(8,2,0)hept-2-ene-7
-one-2-cal step 1 4- (R)-carboxymethyl-1-N-dimethyl-
Synthesis of -butylsilyl-2-azededinone Compound 10
Dissolve 5.17 fl in 800 methanol and stir while cooling with water to prepare 158*t of 0.23 N aqueous potassium solution.
Add dropwise. After stirring at the same temperature for 1 hour, the mixture was heated to room temperature and further stirred for 1.5 hours. After cooling with water and stirring again, 8 Trrtl of normal hydrochloric acid is added, the solvent is concentrated under reduced pressure, and finally freeze-dried to obtain 28 white powder together with the salt. 28 was dissolved in 100% dry fiN, N-dimethylformamide, and while stirring under ice cooling, triethylamine s, isy and 12.2 g of t-butyl-dimethylsilyl chloride were added, and the mixture was warmed to room temperature and stirred for 2 hours. After the reaction, the salt is separated from P and N,N-dimethylformamide is concentrated under reduced pressure. Add ether-water to the residue and dilute with 1N hydrochloric acid.
After adjusting to H2 and stirring at room temperature for 80 minutes, the ether layer was separated, further washed with saturated brine, dried, and concentrated under reduced pressure. When the residue was purified by silica gel column chromatography (chloroform:acetone-5:1), 29
A white solid of 7.12~f is obtained.

Step 2 (3S, 4 liters)-8-(1-hydroxy-1-methylethyl)-4-carboxymethyl-1-N-dimethyl-t
-Butyl 9-80 To 40M1 of dry tetrahydrofuran at 78°C are added 4.8Y of diisopropylamine and 28.0M of n-butyllithium (1,6M solution in hequinane). The solution is stirred for 80 minutes at -78° C. and then compound 29 (4.5 g) dissolved in 16 ml of tetrahydrofuran is added dropwise. After stirring for 40 minutes at -78°C, dry acetone 6
Add 1/1 at a time and stir at -78°C for 80 minutes.
0.2M phosphate buffer (pH 6,8) 80gJ
to stop the reaction.

Ethyl acetate was added to this mixture, extracted and washed with water. After drying, the solvent was removed and the resulting oily substance was subjected to silica gel column chromatography (toluene-anatone = 4:1').
) to obtain compound 80 (4.70 g).

Step 8 (88,4B)-8-(1-hydroxy-1-methylethyl)-4-(8-1)-nitrobenzyloxycarbonyl-2-oxopropyl)-1-N-dimethyl-t
Synthesis of -butylsilyl-2-azetidinone In dry tetrahydrofuran as in step 7 of Example 1,
Compound go (4, sf) was reacted with N,N'-carbonyldiimidazole to form an imitazolide, treated with magnesium salt of malonic acid monoester, and the reaction product was subjected to silica gel chromatography (toluene-acetone = 5
: 1) to obtain compound 81 (5,091).

Step 4 (BS, 4 liters) Synthesis of -3-(1-hydroxy-1-methylethyl)-4-CB-p-nitrobenzyloxycarbonyl-2-oxopropyl)-2-azededinone 2
33 Compound 32 (4,
Compound 83 (141F) is obtained from (821).

Step 5 Synthesis example of (as, 4R)-8-(1-hydroxy-1-methylethyl)-4-(8-p-nitrobenzyloxycarbonyl-2-oxo-8-diazopropyl)-2-azetidinone Compound 8j (8,201) was obtained from compound 88 (8,85F) by the same method as Step 9 of 1.

Step 6 (51, 6S)-p-nitrobenzyl-6-(1-hydroxy-1-methylethyl)-1-azabicyclo(8
, 2,0) Synthesis of hebutane-8,7-dione-2-carboxylate Compound 85 (2,501) was synthesized from compound 84 (8, Of) by the same method as Step 1o of Example 1.
'z get.

Step 7 (517,68)-p-nitrobenzyl-8(2-8-
carbamoylpropylthio)-6-(1-hydroxy-
1-methylethyl)-1-azabicyclo(8,2,0)
Synthesis of -hept-2-en-7-one-2~carboxylate Compound 8
6 (obtains 780ffl.

Step 8 (51L, 68) 8 (2S-carbamoylpropylthio)-6-(1-hydroquine-1-methylethyl)-1-asabicyclo(8,2,0)]hept-2-en-7-one-2carboxylic acid Compound 86 (700 Wjf
) was catalytically reduced using a 10% palladium-carbon catalyst (400 x 19), expressed on an HP-20 column, and lyophilized to obtain a white powder of compound 87 (550 x 1.80 x 1.80).
S, RH, -00, H8), 1.87 (S, 8
)l, O'0HB).

2.75-8.85 (m+ 5H, 04M, 06B, -
80H20).

4, θ ~ 4.48 (m, IH, 0-51 () [R (KB
r) ff-' 1760.1685.1 (ioo, 1
400UVλ Todorox: 800nm Example 5 (5R,68) 8-(S-2-7i/-2-carboxyethylthio)-6-(1-hydroxy-1-methylethyl)-1-azabicyclo(8,2 ,0) Hept-2-en-7-one-2-carboxylic acid Step 1 (5JL 60) p-=tobenzyl-8-((8
)-2-p-2I-lobemethyloxy-2-
p-nitrobemethyloxycarbonylaminoethylthio)-6-(1-hydroxy-1-methylethyl)-1-
Synthesis of azabicyclo(8,2,0)hept-2-en-7-one-carboxylate The compound was synthesized by the same method except that 85 (800~) was used as a raw material instead of compound IO in Step 2 of Example 8. 88 pale yellow solid (1,
1 g) is obtained.

Step 2 (5R,6S)-8-(S-2-amino-2-carboxyethylthio)-6-(1-hydroxy-1-methylethyl)-1-7zabicyclo(3,2,0)hept- 2-
En-7-one Compound 88 as in step 13 of Example 1
By catalytic reduction of (1,09), a pale yellow powder of 89 (280 mm) was obtained.

NMIL(90Δ(H2, D20)δ: IJ2(S
, 8H9-0017B).

1.89 (S, 8H, O0RB), 2.80-8.
85 (m, 5H.

0-4H, C-6H9S 0H2-0), 4.05~
4.50 (m+1ii, 0-5H) IR (KJ3r): 3-1 1750.1640.14
00 water UV λma) c: 804 nm Example 6 (5J, t, 68)-8-(2-8-carbamoylpropylthio)-6-:r-thyl-1-azabicyclo[8
,2,o]hept-2-en-7-one-2-carboxylic acid (8,8,4R) -8-ethyl-4-(2-(0-dimethyl-butylsilyl)-hydroxyethinoly) 1
Synthesis of -N-dimethyl-t-butylsilyl-2-azetidinone Example 1 except that 8tttl of hexamethylphosphoramide and 5-proof ethyl iodide were added in place of the acetalate in step 8 of Example 1. The same reaction and post-treatment as in step 8 were carried out, and the trans-compound 40 was purified by silica gel chromatography (toluene-acetone system: elution using the concentration notation method from 0% to 10% acetone) to obtain 4.7Of compound 40. get.

Step 2 (5 liters, 6 s)-p-nitrobenzyl-6-ethyl-1
-Azabicyclo(8,2,0) to synthesize butane-8,7-thion-2-carboxylate Using compound 40 (14,8y) as a raw material, reactions similar to Steps 5 to 1 of Example 1 were carried out. A pale yellow foam 41 (4,681) is obtained.

Step 8 (5L 68)-8-(2-8-carbamoylpropylthio)-6-ethyl-1-azabicyclo(8,2,0)
Synthesis 8 of hept-2-en-7-one-2-carboxylic acid Compound 41 (
700 lN) was reacted with 2-(8)-carbamoylpropanethiol (40 (lN)) to form a pale yellow powder 42 (710 lN).
). Compound 42 is further deprotected by reduction in the same manner as in Step 13 of Example 1, purified using an HP-20 column, and then lyophilized to obtain 48 (405πf) as a pale yellow powder.

NM几(90Muz, D20) δ: 1.0-1.05
(m, 6Jf.

OH201HB), 2.78-8.82(m, 5H
, 04H, 06U.

S Of: 120), 4.04-4.48 (m, I
H,C! 5H) IR (1 (Br) n-' 17
60. 1690. 1605. 1405 Water UV λmax: 298 nyn Example 7 (511,68)-8-(S-2-amino-2-carboxyetherthio)-6-(R-1-hydroxyethyl)
-1-azabicyclo(8,2,0)hept-2-ene-
7-one-2-carboxylic acid step 1 (88,4B)-3-(1-oxoethyl)-4-(2
-(0-Dimethyl-t-butylsilyl)-hydroxyethylcyl-2-acetidinone for 1-N-dimethyl-t-diisopropylamine and n-butyllithium in dry tetrahydrofuran at -78°C for 15 hours. (1,6M hexane solution) 9. Ottt
The mixture was stirred at the same temperature for 80 minutes, and then compound 8 (4,0y) dissolved in 10H tetrahydrofuran was added thereto. After stirring this bath solution at -78°C for 80 minutes,
The mixture is added to a mixture of 120 vv of N-acetylimidazole in 20 ml of tetrahydrofuran cooled to 20°C. After further stirring at -78°C for 80 minutes, the reaction was stopped by adding 40ml of 0.2M phosphate buffer (pH 6,8). Ethyl acetate was added to the mixture, extracted, washed with water, dried, the bath medium was removed, and the resulting residue was subjected to silica gel column chromatography (toluene-acetone = 2
0:1) to obtain compound 44 (8,85f).

Step 2 (88,4R)-8-(R-1-hydroxyethyl-4
-[2-(0-dimethyl-t-butylsilyl)-hydroxyethylcyl-1-N-dimethyl-t-butylsilyl-
Synthesis of 2-azetidinone In 100 gt of dry ethyl ether, compound 44 (8,
8y) and 1.8y of potassium iodide at room temperature.
Add l. The solution is stirred at room temperature for 8.5 hours, then 3.5 tni of acetic acid is added to terminate the reaction, diluted with 400 tni of ethyl acetate, and insoluble matter is filtered off. The obtained solution is concentrated, and the residue is purified by silica gel column chromatography (toluene-acetone=10:1) to obtain compound 45 (8,10f).

Step 8 (1,68)-8-(S-2-amino-2-carboxyethylthio)-6-(R-1-hydroxyethyl)-1
-Azabicyclo c, s, 2. O) Synthesis of hept-2-en-7-one-2-carboxylic acid 7 Compound 45 is converted to compound 46 in a manner similar to steps 4, 5 and 6 of Example 1. Next, step i of Example 1
7,8,9.10 to obtain compound 47.

021J- Compound 47 was treated in the same manner as in step 2 of Example 8 t),
Compound 48 is obtained by reacting 2-(S)-1)-nitrobemethyloxycarbonylamino-3-mercaptopropionic acid P-nitrobenzyl ester.

Then, in the same manner as in Step 8 of Example 8, the VC compound was contacted to obtain Compound 49.

Patent applicant Kane d: i Chemical Industry Co., Ltd. Agent
Patent Attorney Makoto Asano - 1565-13 Koshigoe, Kamakura City Proceedings of the Amendment Act Showa Fδ 1988/Jl 20th 1981 Patent Application No. 195170 5-(R)-
1-Lance-6-Direct key position 2 2. Name of the invention Manufacture and removal of a private interpolation sheet 3. Person making the amendment Relationship to the case Patent applicant 4, Agent y'A,ヱ

Claims (9)

[Claims] (1) General formula I hole [wherein] "b is an alkyl group, hydroxyalkyl group, B2 is -s -(a■2)n-(3H-coy
(n=l~3, X is a lower alkyl group, amino group or substituted amino group, Y is 0H1OR3 (R3 is alkyl, I; i
;, Aworki/I/ group, aromatic &: group), 5R3 (R3 is an alkyl group, an aralkyl group, an aromatic group), an amino group or a substituted amino group] 5-( whose configuration at the c-5 position is (E))
1'9-) lance-6-substituted cal/<benem compounds and salts thereof. (2) N-carlkyl group in which the M-substituted amino group is represented by N-forminone X, N-acyl group, N-formimidoyl group, kill group or aromatic group),
The compound according to claim 1, which is an N-thiocarbamoyl group represented by an aralkyl group or an aromatic group, and a salt thereof. (3) Claim N in which B4 is methyl/l/&, ethyl group, l-hydroxyethyl group, or l-methyl-1-hydroxyethyl group, and bird is optically active -5aH2c■-coon
)I. A compound according to item 1 and a salt thereof. (4) Claim C in which R1 is a methyl group, ethyl M, l-hydroxyethyl group, or l-methyl-1-hydroxyethyl group, and ■( is optically active -5-CH2-cu-cooti)
I (3. Compounds and salts thereof as described in box 1. (5) R1 is a methyl group, ethyl group, -hydroxyethyl)' group or t-methyl-1-hy)-loxethyl group, and 8 is optically active -S -0If2 (3fi + 001[2) Claim H3: Compounds according to item 1 and salts of (a). (6) General formula I Kill group, bird is -8(CH2)n OHCOY (n=
1 to 3, X is a lower alkyl group, amino group, or substituted amino group, Y is 0H1OR3 (B, 3 is an alkyl group, an aralkyl group, an aromatic group), SR. (R3 is an optically active sulfur-containing residue represented by alkyl A/alkyl group, aralkyl group, aromatic group), amino group or substituted amino group] −(
11-) Lance-6-ftH'f! In producing the Rubabenem compound and its salt, optically active β-(S)-aminoglutarate monomethyl ester is subjected to a ring-closing reaction.
-(S)-Methoxycarbonylmethyl-2-azetidinone was obtained, and then the sample was subjected to alkaline hydrolysis to give 4-(S)-methoxycarbonylmethyl-2-azetidinone.
)-carpogysimethyl-2-azetidinone derivative 3 (representing a protecting group), and then stereospecifically alkylated trans-8-@trans-4-(B)-carpogysimethyl-2-azetidinone derivative 3). 5-(I9-) lance-6-substituted carbapenem compounds represented by the general formula I and their Salt manufacturing method. (7) General formula ■ 几. [In the formula, 几1 is an alkyl group, hydroxyalkyl/l' group, and bird is -8-(0H2)n-Of(-COY(n=l~
B, or a lower alkyl group, an amino group or a substituted amino group,
Y is an optically active sulfur-containing residue represented by 0H10s (Ra1d alkyl group, aralkyl group, aromatic group), 5R3 (R3 is an alkyl group, aralkyl group, aromatic group), amino group or substituted amino group). ] The configuration of the c-5 position represented by! , 'ffi, in producing the 5-CI()-trans-6-substituted carbapenem compound and its salt, optically active β-(S
)-Aminoglutarate moaz methyl ester was subjected to a ring-closing reaction to obtain 4-(S)-methoxycarbonylmethyl-2-azetidinone, which was then reduced to form one 4-(homogeneous hydroxyethyl-2-azetidinone molecule). 1v (representing a protecting group), and then stereospecifically alkylated to trans-8-substituted-4-(I-hydroxyethyl)L/-2-azena (in the formula, ■ represents 1■ or a protecting group). , ni represents an alkyl group, hydroxyalkyl/L/ group) and then oxidizes it to obtain trans-3-substituted-4-(1)-carboxymethyl-2-aze (in the formula, 5-(B)-trans-6-substituted carba/C-nem compounds represented by the general formula I, and their Salt manufacturing method. (8) The production method according to claim 6, in which lithium diisopropylamide is used in an amount of 2 times or more relative to 4-(R)-carboxymethyl-2-azetidinone derivative n (representing a protecting group) during the alkylation reaction. . (9) The production method according to claim 6, wherein the protecting group R is a t-butyldimethylsilyl group. Q(l) The manufacturing method according to claim 7, wherein the protecting group R is a t-butyldimethylsilyl group.