JPS5913785A - Novel beta-lactam compound and its preparation - Google Patents

Abstract

NEW MATERIAL:A beta-lactam compound shown by the formula I (R is H or lower alkyl). EXAMPLE:(5R, 6S)-2-[4 -( Formylimidoyl ) piperidinylthio]-6 -[(R)- 1-hydroxyethyl] penem-3-carboxylic acid. USE:An antibacterial agent. Showing improved activity against Gram-positive and Gram-negative bacteria. A dose is 200-300mg per adult daily. PROCESS:A penem-3-carboxylic acid compound shown by the formula II is reacted with a compound shown by the formula III (R1 is lower alkyl; Y is O or S) or a salt of its acid under an alkali condition at 0 deg.C- room temperature to give a compound shown by the formula I . The reaction under the alkali condition is carried out at 8-12pH, preferably at about 9-10 using an alkalizing agent such as sodium hydroxide, potassium hydroxide, etc. in an organic solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of the general formula (T) [wherein k represents a hydrogen atom or a lower alkyl group]. ] The present invention relates to a β-lactam compound represented by the following and a method for producing the same.

The lower alkyl group in k of the compound represented by the above general formula CI) includes, for example, a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, improvinopen n-butyl, isobutyl, and t-butyl. can be mentioned.

The compounds of the present invention can be made into pharmacologically acceptable salt forms, if desired. Such salts include, for example, lithium, sodium,
Salts of inorganic metals such as potassium, calcium, magnesium or ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, or salts of inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric acids, for example for amidine groups. Alternatively, salts of organic acids such as oxalic acid, maleic acid, and tartaric acid can be used, but sodium salts or hydrochloric acid salts are preferred.

It is a novel compound of the present invention having a β-Rakutei-substituted piperidinylthio group represented by the general formula [■] and a 1-hydroxyethyl group at the 6-position, and has strong antibacterial activity and can be used as a medicine. It is a useful compound.

The method for producing the compound of the present invention will be described below. The compound represented by the general formula [I] is prepared by converting the penem-3-carboxylic acid compound represented by the formula [■] under alkaline conditions into the general formula [TII] [where k has the same meaning as above, k represents a lower alkyl group, and Y represents an oxygen atom or a sulfur atom. ] It can be produced by reacting with a compound represented by the following or a salt thereof with an acid.

Examples of R in the compound represented by the above general formula (1) include lower alkyl groups having 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, inpropyl, n-butyl, and isobutyl. is preferably methyl or ethyl.

Examples of salts with acids include salts of hydrohalic acids such as hydrochloric acid, hydrobromic acid, and hydroiodic acid, but salts with hydrochloric acid are preferred.

The reaction under alkaline conditions can be carried out at a pH in the range of 8 to 14, preferably around pH 9 to 10. Alkaline metal hydroxides such as potassium hydroxide, calcium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, sodium carbonate, potassium carbonate as alkaline reagents used in the reaction. Preferably, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc. may be mentioned.

Further, this reaction is preferably carried out using water as a solvent, but it can also be carried out in a mixed solvent of water and an organic solvent. Organic solvents used include methanol, ethanol, n
-Alcohols such as propatool, ethers such as tetrahydrofuran and dioxane, dimethylformamide, acetonitrile, etc. can be mentioned.

The reaction can be suppressed or promoted by appropriately cooling or heating the reaction temperature, and a suitable temperature can be said to be 0° C. to room temperature.

After the reaction is completed, the resultant can be taken out using ordinary organic chemical methods. A reaction product can be obtained by separating the portion and freeze-drying it.

and water, methanol, ethanol, n-propertool,
It can be produced by reaction in an inert solvent such as a solvent such as dioxane, tetrahydrofuran, or a mixed solvent thereof.

The trithiocarbonate potassium salt represented by the above formula (7) used as a raw material is a mercaptan compound represented by the formula (9)% ([in the formula, PNZ has the same meaning as above]) and carbon disulfide. and potassium hydroxide according to a conventional method.The raw material mercaptan derivative (9) can be easily produced, for example, by the following route.

[Wherein, PNB J and PNZ have the same meanings as above. ]

Step (b): Compound (3) has, for example, formula (8)% formula%
It can be produced by heating the compound represented by (81) and compound (2) in an inert solvent such as benzene or toluene under anhydrous conditions.

Step (C): Compound (4) is converted into a chloride by reacting compound (3) with thionyl chloride in the presence of a base such as 2,6-lutidine, pyridine, triethylamine, etc., and then in an inert solvent such as tetrahydrofuran. It can be produced by reacting with triphenylphosphine to induce a phosphoniuno salt, followed by treatment with a base such as sodium bicarbonate, sodium carbonate, potassium carbonate, etc.

Step (d): Compound (5) is heated in an inert solvent such as benzene, toluene, xylene, or 0-xylene in the presence of an antioxidant such as hydroquinone.
).

Step (e): Compound (5) is reacted with hydrogen gas in an inert solvent such as methanol, ethanol, tetrahydrofuran, dioxane, water, or a mixed solvent thereof in the presence of a catalyst such as Pd/C to form a compound by so-called catalytic reduction. (6)
I can guide you to.

The above-mentioned raw material azetidinone derivative (1) is disclosed in JP-A-55-1
Although it can be synthesized according to the method described in Japanese Patent No. 53789, it can be easily produced by a completely new production method using a series of new derivatives as shown below.

(10) (l])・
0ri 03) (14)
(11 [wherein, D
AM represents a di(P-anisyl)methyl group, and PNB and PNZ have the same meanings as above. ] Each step will be explained below.

Step (f): Compound OD is a Schiff base aa+wo derived from n-butylglyoxylate and di(p-anisyl)methylamine by a known method, an inert compound such as methylene chloride, chloroform, benzene, toluene, etc. It can be produced by treatment with crotonoyl chloride in a solvent in the presence of an organic base such as triethylamine, pyridine, lutidine, or 1,5-diazabicyclo(5,4,'0)undecene-5 (DBU).

Step (g): Compound Oz can be produced by hydrolyzing the ester group of compound (111) with acid or alkali.

Step (h): Compound αJ can be produced by treating compound α■ with mercuric acetate and then with sodium borohydride in an inert solvent such as tetrahydrofuran, dioxane, acetonitrile, water, etc. or a mixed solvent thereof. can.

Compound 04) can be produced by treating step (i+: compound 03) with lead acetate in an inert solvent such as benzene, toluene, acetic acid, or dimethylformamide. At this time, reaction aids such as pyridine, sodium acetate, potassium acetate, etc. may be added as necessary.

Step (j): Protect the hydroxyl group of compound 0a with an acylating agent such as P-nitrobenzyl chloroformate, and add it to an inert solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, water, etc. or a mixed solvent thereof. , ceric ammonium nitrate
) can produce compound (1).

Note that the optically active derivative (1) is the compound qri β-(-)-
After esterifying with menthol and optically resolving the obtained ester, it was subjected to hydrolysis to obtain an optically active compound, and then (h).

It can be manufactured through the steps (i) and (j).

The novel β-lactam compound of the present invention represented by the general formula [■] is suitable for use in Durham-positive bacteria such as Staphylococcus aureus, Staphylococcus evidermidis, Streptococcus pyogenes, and Streptococcus fuecalis, Escherichia coli, and Proteus. - It has extremely excellent antibacterial activity against a wide range of pathogenic bacteria, including Durham-negative bacteria such as S. mirabilis, Serratia marcescens, and Pseudomonas aeruginosa, making it a useful compound as an antibacterial agent.

Dosage forms for using the compound of the present invention as an antibacterial agent to treat bacterial infections include, for example, tablets, capsules,
Examples include oral administration using a syrup, etc., or parenteral administration via intravenous injection, intramuscular circular injection, rectal administration, etc.

The dosage varies depending on symptoms, age, body weight, dosage form, number of administrations, etc., but is usually about 200 to 300 doses per day for adults.
Administer 0”r once or in divided doses.

The amount can be reduced or increased as necessary.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is of course not limited to these in any way.

Example 1 5,6-trans isomer of 2-(4-piperidinylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid 450 w9 0.04 M phosphate buffer (pH 7,
4) Add 50 mZ and 4N- while stirring under water cooling.
A sodium hydroxide solution was added dropwise to adjust the pH to 12, and stirring was continued until complete dissolution. Next, add 1.2 g of egurformimidate hydrochloride in small portions in 2 to 3 portions.
The pH is kept at 10 in each case by adding dropwise 4N sodium hydroxide solution. After stirring for 30 minutes, 2N-hydrochloric acid was added dropwise to p.
H7.0 and this solution was MCI GEL CHP.
After subjecting to column chromatography using -20P 200- and eluting inorganic salts and impurities with water, 10%
The fraction eluted with methanol-water was collected and freeze-dried to produce 2-(4-(formimidoyl)) as a colorless powder.
5,6-trans isomer of piperidinylthio]-6-(1-hydroxyethyl)penem-3-carboxylic acid 262
mq was obtained.

IR (Cr1): 3350 (br), 1763
, 1700.

ax 1566, 1360, 12B0, 1120Uv>
14zOnm: 256', 320ax NMRδ (D20): 1°27 (3H, d, J=5.5
Hz).

3.89 (IH, dd, J=1.2 and 6.511
z), 4.22(IH,quxnt, J=
6, 5") + 5-65 (IH+ d+J=1゜2Hy,), 7.73 (IH,') and (5R, 6
S)-2-(4-piperidinylthio)-6-((R)
-1-hydroxyethyl) penem-3-carboxylic acid (specific optical rotation [α) 26 + 79.4° (C-0°045,
(5R,6S)-2-[4-(formimidoyl)piperidinylthio)-6-((R)-
1-Hydroxyethyl)penem-3-carboxylic acid was obtained.

Specific optical rotation [α]ゎ+47.7° (C-0゜073.H
2O) (I R, NMR, UV i'! Above (7) 5
．． Example 2 500 μl of 5.6-trans isomer of 2-(4-piperidinylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid was added with 0.04 M phosphate buffer. liquid (pH 7,4)
50- was added thereto, and while stirring under water cooling, 4N sodium hydroxide solution was added dropwise to adjust the pH to 12, and stirring was continued until complete dissolution. Next, ethyl acetimidate hydrochloride 1
Add ゜05F in small amounts in 2 to 3 times, each time adding 4
The pH was maintained at 10 by adding a solution of IJ (N-hydroxide) dropwise. After stirring for 15 minutes, 2N-hydrochloric acid was added dropwise to adjust pI (
7, Q, and this solution is MCI GEL CHP 2
After column chromatography using 0P 200-, inorganic salts and impurities were eluted with water, and the fractions eluted with 10q6 methanol-water were collected and freeze-dried to obtain 2-[4-(acetimidoyl)piperidinylthio] as a colorless powder. ]-6-(1-Hydroxyethyl)penem-3-carboxylic acid, the 5.6-) lance isomer 388 was obtained.

IRKBr(n-1): 3400(br), 1
765, 1620.

ax 1572, 1362, 12B2, 1125UV
A"20nm: 255, 320laX NMRδ (D20): 1.27 (3H, d, J=
6.5H2).

2.26 (3H, S), 3.89 (IH, dd, J=
1.2and5,5Hz),4,22(IH,q
uint, J = 5.5Hz).

5.65 (IH, d, J=1,2H2) and (5R,6
8)-2-(4-piperidinylthio)-6-((R)-
1-hydroxyethyl) penem-3-carboxylic acid (specific optical rotation [α], +79.4° (c=0.045, H2
O) ) to (5R,6S)- by the same process as above
2(4-(acetimidoyl)piperidinylthio]-6
-((R)-1-hydroxyethyl)penem-3-carboxylic acid was obtained.

Specific optical rotation [α), +49.1° (c-0, 057
, "20) (I R, NMR, UV are consistent with the above-mentioned 5,6-trans form.) Example 3 The same operation as in Example 1 was performed using the 5,6-trans isomer and ethylpropionimidate hydrochloride to obtain colorless powder of 2-(4-(propionimidoyl)piperidinylthio]-〇-(1-hydroxyethyl). Penem-3-carboxylic acid was obtained.

IRKBr (C1s-1): 3400 (br),
1765, 1615.

ax 1570, 1365, 1120 UV zH20nm: 254, 319aX Reference Example 1-il+ Schiff base was removed from di-P-anisylmethylamine (IOS') and n-butylglyoxylate (7,31') by toluene azeotropic dehydration. Make the toluene solution (about 6
00 rnl), triethylamine (6,2y)
and crotonoyl chloride (5,12) was added to toluene (2
5-) was added dropwise at 70°C over about 1 hour, and the mixture was stirred for 2 hours. After cooling, washing with water, washing with 2N hydrochloric acid, washing with heavy sodium chloride, washing with water, drying with sodium sulfate, concentration, and silica gel chromatography to obtain 1-(di-P-anisylmethyl).
-3-ethynyl-4-0-butylcarboxy-2-azetidinone was obtained.

IR""3 (n'): 1758.1615.1
252.1180゜m x 1030, 930, 825 NMRδ (cDck3): 0.87 (3H, br
, t, J=6) 1.0 to 1.7 (4H, m), 3.
78 (6H, 8), 5.1~5.8 (3H, m)
, 5.77 (IH,S) Reference Example 112+ n-butyl ester derivative (0°5F) was converted into lN-NaO
H aqueous solution (1,2i)-tetrahydrofuran (15m/
)-methanol (15ml) and stirred at room temperature for 2 hours. 2N-hydrochloric acid (0,7,7) was added, and after concentrating to about 1/4, water was added and extracted with ether. After re-extracting with alkaline water, the aqueous layer was re-extracted. The aqueous layer was acidified with hydrochloric acid, extracted with ether, washed with water, dried with mirabilite, and the solvent was distilled off to obtain I-., (di-p-ayucylmethyl)-3-ethynyl-4-carboxyl-2-azetidinone.

IR””3 (n-1): 1753, 1612
, 1297, 1245°ax 1170, 1109, 1027, 828NMRδ
(CI)Cn3): 3.80(6)(,S),5.
1-5.9 (3H.

m), 5.83 (IH, s), 8.64 (iH
, Reference Example 1-(3) Ethynyl derivative (i, oy) was dissolved in detrahydrofuran (8.8ml), and water (2.0m/) and mercuric acetate (0.9y) were added. The mixture was heated under reflux for 8 hours.

lN-NaOH water (7,2 ml) was added at 0 °C, and sodium borohydride (0, IP) was added to lN-NaO.
Add dropwise a solution of 1 H water (1 m/) and stir at the same temperature for 5~
After stirring for 6 minutes, the mixture was neutralized with 6N hydrochloric acid, ether was added, and the mixture was filtered through Celite. 1-(
P-anisylmethyl)3-(1-hydroxyethyl)-4-carboxyl-2-azetidinone (0,859
) was obtained.

Nu'ol -1.

IR' (n), 3250, 1750, 17
23,1515°ax 1305, 1250, 1177, 1030.

35 NMRδ(CDCJ73); l, 22(3
I-1, d, J-6Hz).

3.18 (IH, m), 3.72 (6I4.8)
, 4.10(11(.

d. Lead acetate (5,39) was added in several portions. After stirring for 1 hour, ethylene glycol was added to stop the reaction, ethyl acetate and saturated brine were added, insoluble materials were removed by filtration through Celite, extraction with ethyl acetate, washing with water, drying with sodium sulfate, solvent distillation, and silica gel chromatography. , I-(di-P-anisylmethyl)-3-(1-hydroxyethyl)
-4-acetoxy-2-azetidinone (3,03F)
I got it.

IROI”3 (cm-1): 1752, 135
7, 1302, 1242°ax 1174, 1028, 953 NMRδ (CDCj?3): 1.26 (3H, d
, J=5.5Hz).

1.90 (3H, !1), 3.07 (IH, brOad
dJ=5.5Hz), 3.78 (6H, $), 4
．． 07 (IH, m).

5.83 (IH, broads).

5.1313 (IH, brond s) Reference Example 1151 Hydroxyethyl derivative (5,3F) was dissolved in dichloromethane (18rnl), 4-dimethylaminopyridine (1,989) was added, and P-nitropenzyl chloroformate was dissolved. A solution of (3,529) in methylene chloride (9 ml) was added dropwise, and the mixture was stirred overnight at room temperature. I-(di-P-anisylmethyl)-3-(1
-p-nitrobenzyloxycarbonyloxyethyl)
-4-acetoxy-2-azetidinone was obtained.

11m-1 1R (cm): 1770 (shoulder)
, 1740°ax 1610, 1583, 1020, 850.

818, 735 NMRδ (CDC13): 1.42 (3H, d, J
=6), 1.85 (3H.

s), 3.28 (IH, br, d, J=6), 5.22
(2H,s).

5.87 (IH, 5), 6.11 (IH, br, s) Reference Example 1-<61 N-(di-P-anisylmethyl) derivative (6,061)
was dissolved in 10% H2O-acetonitrile (9M) and dissolved in ceric ammonium nitrate (ceric ammonium nitrate).
monium n1trate.

12.11) was added in several portions over 1 hour at room temperature, and the mixture was further stirred for 30 minutes. Add water, extract with ethyl acetate, wash with water, dry with sodium sulfate, remove solvent, and chromatograph on silica gel.
-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone was obtained.

IR”m(n-1): 1774, 1745, 160
2,1513°ax 1344, 125B, 1029, 843NMR
δ (CDC/, s): 1.45 (3H, d, J=6
) 12.09 (3H, s), 3.37 (IH, br,
d, J=6. b).

5.87 (IH, br, s), 5.9 (5 (IH, b
r, s) Reference example 1-(71 3-(1-P-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone 1.55
F was dissolved in dioxane 15-, and 4-(1-P-nitrobenzyloxycarbonyl) was added thereto under an argon atmosphere.
Piperidyl trithiocarbonate potassium salt 1.902
A solution of 15 rnl of dioxane and 15 ml of H2O was added at room temperature, stirred at the same temperature for 1 hour, methylene chloride was added to the reaction solution, washed with water, dried with sulfur salt, the solvent was distilled off, and the residue was purified by silica gel chromatography. -P-nitrobenzyloxycarbonyloxyethyl) -4-(4-(1-p
-nitrobenzyloxypiperidinyl)-thiocouthiocarbonylthio-2-azetidinone was obtained.

XRCHC13(♂1): 1772,1685,1
515,1340°ax 25O NMRδ(CI)Cn,s): 1.45(3H
, d, J=6Hz).

3.43 (IH, dd, J=2.5.6H2).

5.23 (2H, g), 5.62 (IH, d, J=2.
5Hz).

7.50 (2H, d, J=9Hz), 8.17 (2H,
d, J = 9Hz) The raw material trithiocarbonate potassium salt is as described below [
Reference Example 3].

Reference example 1-+81 P-nitrobenzylglyoxalate monohydrate 0.8
After azeotropic dehydration of 29 with dry benzene, dry benzene 5o- was added thereto. Add 3-(1-p) to this solution.
-nitropenzyloxycarbonyloxyethyl-4-
[4-(1-p-nitrobenzyloxypiperidinyl)
-thio]-thiocarbonylthio 2-azetidinone2.
A solution of 38 f of dry benzene 5o- was added and refluxed for 2 hours to remove the solvent, and the residue was diluted with 53 m/d of dry detrahydrofuran.
, 1.159 of 2,6-lutidine was added thereto, 1.285' of thionyl chloride was added at -15°C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 minutes. Methylene chloride was added to the reaction solution and IN-
Washed with hydrochloric acid, washed with water, dried with sulfuric acid, the solvent was distilled off at room temperature, 1.5% of dry tetrahydrofuran was added to the residue, 1.88% of triphenylphosphine was added and dissolved, and after standing under argon overnight, the reaction solution was Add methylene chloride to saturated hydrogen carbonate) Wash with IJum aqueous solution, wash with water, dry with sulfuric acid,
The solvent was distilled off, the residue was purified by silica gel chromatography, and 3-(1
-P-nitrobenzyloxycarbonyloxyethyl)
-4-(4-(1-P-nitropenzyloxycarbonylbiperidinyl)-thio]-thiocarbonylthio-1-
(1-p-nitrobenzyloxycarbonyl)triphenylphosphoranylidenemethyl-2-azetidinone was obtained.

1435, 1342, 1250, 1105.

1070.1008 Reference Example 1-+9+ a) 3-(1-P-nitrobenzyloxycarbonyloxyethyl)-4-(4-(1-P-nitrobenzyloxycarbonylpiperidinyl)-thio)-thiocarbonylthyl t-1-(1-P-Nitropenzyloxycarbonyltriphenylphosphoranylidenemethyl-2-azetidinone 1.757% was dissolved in 5781n! of dry 〇-xylene, and a catalytic amount of hydroquinone was added thereto under a nitrogen stream for 9 hours. The solvent was refluxed for hours, the residue was purified by silica gel chromatography, and 2-(4-(1-p-nitrobenzyloxycarbonylpiperidinyl)-thio)-6-(1-P-nitrobenzyloxycarbonyloxyethyl)penem- A 5°6-trans isomer and a 5,6-cis isomer of 3-carciboxylic acid P-nitrobenzyl ester were obtained.

5.6-trans isomer IR knee lδ (>-1): 1785, 1722
, 1695.

1601, 1518, 1340.

105 Core set δ (CDC13): 1°5o (3H+dp J
=6.5)(Z).

3, gl (IH, dd, J = 7.5 and 2 Hz).

5.21 (2H, g), 5.24 (2H, s).

5.30 (2H, AB (1 (7) center, J-14H2)
.

5.65 (IH, d, J = 2H1) 5.6-cis isomer IRCI4''(Cm'): 1785, 1740
, 1700.

ax 1605.1520.1342°101 05Nδ(CDC13): 1.60(31(,d
, J = 5.5Hz).

4.13 (IH, dd, J = lQ, 5 and 4Hz
).

5.21 (2H, I), 5.24 (2H, II) 5.2
6 (center of 2H, AB'l, J=14°5Hz).

5.73 (IH, d, J = 4) iz) b-1) 2
-(4-(1-p-nitrobenzyloxycarbonylpiperidinyl)-thio)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)penem-3-carboxylic acid P-nitrobenzyl ester 5°6 - Dissolve 200"l of the trans isomer in 9-tetrahydrofuran, add 1st ethanol and 10rnl of 0.025M phosphate buffer (pH 6,8), and connect with normal pressure water using 5% palladium-carbon 600ml. The mixture was stirred for 1 hour.

After the reaction was completed, the catalyst was removed, washed with water, the washed liquid and the washed liquid were combined, concentrated under reduced pressure to 5 to 10, and MCI-GE
The fraction was subjected to column chromatography using 5 ml of L CHP-2Q P and eluted with 7.10 titanol-water, and the fraction was collected and freeze-dried to obtain colorless powder 2.
The 5.6-) lance isomer (22■) of -(4-biperidinylguo)-6-(1-hydroxyethyl)penem-3-carboxylic acid was obtained.

IRKBr(z-1), : 3400(br), 1
765, 1625.

ax 1560, 1370, 1282 UV lH2O: 255, 320 ax nm NMRδ (D2o): 1.25 (3H, d,
J=6)IZ).

3-89 (IH+dd, J-1, 5and (3Hz).

5.63(1)(,d,J=1.5H7)b-2)
5° of 2-(4-(1-p-nitrobenzyloxycarbonylpiperidinyl)-thio)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)penem-3-carboxylic acid p-nitrobenzyl ester From the 6-cis isomer (140 K), 2-(
5,6-cis isomer of (4-piperidinylthio)-6-(1-hydroxyethyl)penem-3-carboxylic acid (30
~) was obtained.

IRKBr(n-1): 1770, 1612,
1565.

ax 1372, 1278, 1125.

075 UV lH2O: 255, 318 axnm NMRδ (D20): 1-32 (3”1dJ-7
HQ13.91 (IH, dd, J=4.5and 1Q
Hy).

5.7Q(l)(,d,J ~4.51(Q Reference Example 2-
111 Carboxylic acid derivative Cd1 form) (10,24F)
To a solution of methylene chloride (45rn!), dimethylformamide (1 drop), oxboryl chloride (4,25f)
) in methylene chloride (5 rnl) was added dropwise at room temperature for 20 minutes. After stirring at the same temperature for 1.5 hours, the solvent was distilled off. The residue was dissolved in methylene chloride (30ml), and added to a solution of l-←)-menthol (4,599), 4-dimethylaminepyridine (3,58F) in methylene chloride (30rnl) under water cooling for 2 hours. Stir. The reaction solution was diluted with 2N-
The mixture was washed with hydrochloric acid and saturated aqueous sodium bicarbonate, and then dried with sodium sulfate and the solvent was distilled off. By adding methanol to the obtained residue, heating and dissolving it, and cooling it, the 4-di)-menthol ester of the carboxylic acid derivative Cd1 (the two isomers have a relative ratio of 1).
=1) crystals (mp, 96-97°C) were obtained.

(3S,4R)-1-(di-p-ayucylmethyl) was obtained by heating and dissolving the above crystals in methanol (400ml), cooling to about -5°C, and collecting the precipitated crystals.
-3-ethynyl-4-l -H-menthylcarboxyl-2-azetidinone was obtained. By recrystallizing with methanol, a pure product (mp, 114-115℃, specific optical rotation [α), -t-20,2° (c=0.26.C
lIc13) ) was obtained.

In addition, the above-mentioned 4-F)-menthol ester having a ratio of about 1:1 between the two isomers was purified by high performance liquid chromatography (column: Lichrosorb S 1-60, solvent 1.5% inpropanol-n-hexane). were also separable.

(3S,4R)-1-(G-P-anisylmethyAz
) -3-ethynyl-4-menthylcarboxyl-2-
The ester group of azetidinone was hydrolyzed in the same manner as described in Reference Example 1-(2).
)-1-(di-P-anisylmethyl)-3-ethynyl-
4-carboxyl-2-azededinone (specific optical rotation [α)
, +63.3° (c=0.12.G(C63))
I got it.

Reference Example 2-(21 (as, 4R)-1-(di-p-ayucylmethyl)-3-ethynyl-4-carboxyl-2-azetidinone [Reference Example] -J3)) [Reference Example 1- +4
By sequentially performing the reactions of 1) (3S, 4R)
-1-(di-P-anisylmethyl)-3-((R-1-
1-hydroxyethyl)-4-acetoxy-2-azetidinone (specific optical rotation [α], + 26.0° (c ~ 0
．． 04, CHCnz)) was obtained.

Furthermore, using the above-mentioned optically active acetoxy derivative,
[Reference Example 1-(51), [Reference Example 1-(3S) by sequentially performing the reactions of (6+3).

4R)-1-(di-P-anisylmethyl)-3-((R
)-1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (specific optical rotation [α), +40.56 (C-0°as, CHCn,
)), (3S,4R)-3-((R)-1-
(nitropenzyloxycarbonyloxyethyl)-4-
Acetoxy-2-azetidinone (specific optical rotation (α), +3
6.6゜(c=0.09,chxcl,,))
I got it.

Reference Example 2-+31 In the same manner as in the above [Reference Example 1-17)), (3S, 4R
) from 3-(4-1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone, (3s.

4R)-3-((R1-1-p-nitrobenzyloxycarbonyloxyethyl)-4-(4-(1-p--nitrobenzyloxypiperidinyl)-thiotwo-thiocarbonylthio-2-azetidinone I got it.

Specific optical rotation [α], +113.5° (c-0.75, C
(3S, 4R
)-3-()-1-p-nitrobenzyloxycarbonyloxyethyl-4-(4-(1-P-nitrobenzyloxypiperidinyl)-thio2-thiocarbonylthio-2-azetidinone (3S, 4R)-3-((R
)-1-P-nitrobenzyloxycarbonyloxyethyl)-4-(4-(1-p-nitrobenzyloxycarbonylbiperidinyl)-thiotwo-thiocarbonylthio-1-(1-p-nitrobenzyloxycarbonyl) )
-triphenylphosphoranylidenemethyl-2-azetidinone was obtained.

Optical rotation [α), +70.4° (c = 0.32, c
Hck3) (IR matches that of the compound obtained in [Reference Example 1- +81)) Reference Example 2-(5+ (3S, 4R)-3-[(R)-1-P-nitrobenzyloxycarbonyloxy)- 4-(4-(1-P
-nitrobenzyloxycarbonylbiperidinyl)-thio)-thiocarbonylft -1-(1-P-nitrobenzyloxycarbonyltriphenylphosphoranylidenemethyl)-2-azetidinone as described above [Reference Example 1-(9
By processing in the same manner as a)), (5R,6S)
-2-(4-(1-P-nitropenzyloxycarbonylhyheridinyl)-thio) -6-[(R1-1-p-
(nitrobenzyloxycarbonyloxyethyl)penem-3-carboxylic acid P-nitrobenzyl ester (specific optical rotation [α), +80.8° (c=o, 124°CH
Cl3), IR, and NMR were as described above [Reference Example 1-(9a)
) and (5S, 6S)-2
-(4-(1-P-nitrobenzyloxycarbonylbiperidinyl)-thio)-6-((R1-1-P-nitrobenzyloxycarbonyloxyethyl)penem-3-
Carboxylic acid P-nitrobenzyl ester (specific rotation [α
) D-71,9° (C=0.095, at-ice,
) IR and NMR were the same as those of the cis isomer obtained in Reference Example 1 (911)).

Furthermore, (5R,,6S)-2-(4-(1-P-nitropenzyloxycarbonylbiperidinyl)-thio)-
From 6-((8)-1-P-nitrobenzyloxycarbonyloxyethyl)penem-3-carboxylic acid P-nitrobenzyl ester, the above [Reference Example 1-(9b-1)
] (5R,65)-2-(4-piperidinylthio)-6-C(R)-1-hydroxyethyl)penem-3-carboxylic acid was obtained.

(Specific optical rotation [α), + 160.6° (c = 0.
07, H2o) Reference Example 3-(ll Piperidone Monohydrate Hydrochloride 6.11
', N, N-dimethylaminopyridine 10.79
was dissolved in a mixed solution of 120 parts of tetrahydrofuran and 10 parts of water, and then a solution of 25 parts of tetrahydrofuran (P-nitropenzyl chloroforme) 9.52 was added dropwise under ice-cooling, and the solution was left as it was for 30 minutes, and further stirred at room temperature for 10 minutes. Stir for hours. The reaction solution was diluted with ethyl acetate, washed successively with IN-hydrochloric acid and water, dried with sodium sulfate, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of isopropyl ether and ether to obtain 1-(P
-nitrobenzyloxycarbonyl)-4-piperidone was obtained.

IRNujol (♂1): 1715, 1690,
1512,1443°aX 1340, 1232, 1122 NMRδ (CDC43): 2.47 (4H, t,
J=6H2) 13.83 (4H, t, J=6Hz).

5-27 (2■1.') t 7-50 (2H,
d, J=9)1z).

8.17 (2H, d, J = 9H1) Reference Example 3- (21 1-(p-nitrobenzyloxycarbonyl)-4-piperidone 5.465' was dissolved in a mixed solution of 54 methanol and 27 m/27 m of tetrahydrofuran. 373 Mg of sodium borohydride was added to this, stirred at 0°C for 10 minutes, water was added to the reaction solution, extracted with ethyl acetate, washed with water,
The residue was dried and the solvent was distilled off to obtain 1-(p-nitrobenzyloxycarbonyl)-4-hydroxypiperidine.

IRNu"1 (z-1): 3420, 1670, 1
510,1340゜ax 1272, 1230, 1077 Reference Example 3-131 1-(p-nitrobenzyloxycarbonyl)-4-hydroxypiperidine 10.54 F dried pyridine 10
To this solution was added 14.35 f of P-) luenesulfonyl chloride at 0°C, and the mixture was stirred at 25°C for 23 hours. Water was added to the reaction solution, and ether-methylene chloride (9:1) Extraction with a solvent, the extract was diluted with saturated saline, IN-
The mixture was washed with hydrochloric acid, saturated brine, and saturated sodium bicarbonate in this order, dried with sulfur salt, and the solvent was distilled off to obtain 1-(p-nitrobenzyloxycarbonyl)-4-(P-toluenesulfonyloxy)piperidine.

IRNu”1(o-1): 1702,1512,1
340,1225°ax 173 NMRδ (CDC113) ”I-78(4H1
q* J-6H1) +2.47 (3H, s), 3.
13-4.00 (4H, m).

4゜75 (IH, quintet), 5.22 (2H
,I).

7.37 (2H, d, J=8H7).

7.50 (2H, d, J=9H2).

8.22 (2H, d, J=9H2) Reference Example 3-(4) 1-(p-nitrobenzyloxycarbonyl)-4-
(p-)luenesulfonyloxy)piperidine 14.7
8F was dissolved in 222 m/222 m of acetone, 12°71 F of sodium iodide was added to this solution, and the mixture was refluxed for 23 hours. 1-(p-nitrobenzyloxycarbonyl)-4-iodopiperidine was obtained by washing in this order with an aqueous solution of IJ and saturated brine, drying with sodium chloride, and distilling off the solvent.

IRN11j0'(n''): 1685, 1512
．． 133B, 1265°ax 225 NMRδ (CDC4,): 2.02(4H, (1
, J=6H7,).

3.56 (4H, q, J = 5) (z).

5.22 (2H, s), 7.50 (2H, d, J=9
HQ, 8.18 (2) (, clJ = 9 Hz) Reference Example 3-+51 50 To a suspension solution of 1.219 nl of sodium thihydride and 23.51 nl of dry dimethylformamide, under a nitrogen stream,
A solution of 2.37 F of thioacetic acid and 23.5 m/2 of dry dimethylformamide was added at 10°C, stirred at room temperature for 20 minutes, and 1-(P-2l-lobenzyloxycarbonyl)-4-iodo was added to the solution. A solution of piperidine 9.34 P and dry dimethylformamide 47- was added, stirred at room temperature for 20 hours, water was added to the reaction mixture, and extracted with ethyl acetate.
Washing with 0% sulfite aqueous solution, washing with water, drying with sulfur salt, distilling off the solvent, and crystallizing the residual liquid from ether gave 1-(p-nitrobenzyloxycarbonyl)-4-thioacetoxy-piperidine.

[11m-1.

TR,max(clA), 1710,1695,1
520,1343°1210,1112 NMRδ (CDC/2.): 1.17-2.20
(4H, m).

2.33 (3H, m) 2.90-4.20 (5H, m)
.

5.21 (2H, i), 7.47 (2H, d, J
=9HQ.

8.17 (2H, d, J = 9HQ 1-(p-nitrobenzyloxycarbonyl)-4-thioacetoxypiperidine 3.15 F in methanol 12
Under an argon atmosphere, IN-sodium hydroxide aqueous solution 8.9- was added at room temperature, stirred at the same temperature for 10 minutes, methylene chloride was added to the reaction solution, the methylene chloride layer was washed with water, and dried after drying. The solvent was distilled off to obtain 1-(p-nitrobenzyloxycarbonyl)-4-mercaptopiperidine.

Reference Example 3-+7+ 1-(p-nitrobenzyloxycarbonyl)-4-mercaptopiperidine 1.54 F was dried in ethanol 25
To this was added a solution of 292~ potassium hydroxide in dry ethanol 3- under an argon atmosphere at 0°C, stirred at the same temperature for 30 minutes, added 792~ carbon disulfide, and stirred at room temperature for 3 hours. The precipitated crystals were collected, washed with ethanol, and dried to obtain 4-(1-p-nitrobenzyloxycarbonyl)piperidinyl trithiocarbonate potassium salt.

11: Q' (Volunteer) Akira (August 1157 310 Special r (Agency Chief Wakasugi Aio Di'>I Shin ('l)
O) Display Show [115 Fui 1! Brother i'J'll;
1910 1″12 Invention Q) Name 11 New β-lactam compound and its manufacturing method 3 Relationship with Sen 11ro・d and 11T('l Patent applicant I 1 Location 51 Kitahama, Santo-ku, Osaka't=115 Address name: <2oq
)'A Yukagaku 1do Co., Ltd.? 1 Representative name Hijikata
Attorney Takei (1 location, Higashi-ku, Osaka, 51-15-5, 7-rho, Correct as per the error.

-H

Claims (2)

[Claims] (1) General formula [wherein k represents a hydrogen atom or a lower alkyl group] ] A β-lactam compound represented by these and a pharmacologically acceptable salt thereof. (2) A compound represented by the formula and the general formula [wherein k represents a hydrogen atom or a lower alkyl group, R1 represents a lower alkyl group, and Y represents an oxygen atom or a sulfur atom. ] A general formula characterized by reacting a compound represented by the following or a salt thereof with an acid under alkaline conditions [where K has the same meaning as above. ]
- A method for producing a lactam compound.