JPS6153283A - 2-oxo-1-azetidinesulfonic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

This invention relates to sulfo/forward derivatives (azetidine derivatives) and salts thereof. The novel azetidinone derivative of the present invention has the following formula (where n is 2
and 3) and pharmaceutically acceptable salts thereof. The compound of the present invention is represented by formula (l). The stereochemistry of the azetidinone ring is such that the acylamino group at the 3-position is β
At the α-position, the quaternary fluoromethyl is coordinated at the α-position and has a trans structure. The oxoimino at the 3-position acylamino group can have a g-t or O geometric isomer structure, but the compound of the present invention has a Z structure as shown in Formula 1 [1]. Recently, a monocyclic β-lactam anti-freeze □1 study with a 2-azetidinone skeleton having an acylamino group at the 3-position and a sulfone Uk at the 1-position was reported A, Imada et al. C, Nature + 28
9 +590 (1981) ) and R+ B, 5y
kes et al. (: Nature +2, 489 (19
81) ) can be discovered independently by the two / loops,
It was named Monobatatum by the Ministry of Dust. After that, natural β
- A large number of monobactamy monuments were synthesized from lactams or by old methods, and JP-A-55-1646'7
1, #Kaisei 55-164672, JP-A-56-1
25362. Lrf@Sho 56-133259, 1982-133260. 56-135465°Fu Kaisho 56-138169. Tokikai Showa 56-139454
．． Japanese Patent Publication No. 5'7-98258. Japanese Patent Publication No. 57-11856
0. Japanese Patent Publication No. 57-131758, +P Publication No. 57-13
1759. JP-A-57-1" 5162゜ JP-A-57-2
121'79. Japanese Patent Publication No. 58-8060. and JP-A-58-18381. The present inventor conducted intensive research on compounds in which a fluoromethyl group is substituted in the 4-position of the azetidinone moiety in the α-coordination, and the ananolamino group in the 3-position has a trans (3S, 4R+ structure), and found that they exhibit strong antibacterial activity. discovered that it was useful as a medicine, and filed an application for a watch (Japanese Unexamined Patent Publication No. 1983
-208288). The present inventors are (38, 4R)-(-)-3-((Z!-2-(2
-Amino-4-thiazolyl I -2-(1-carboxy-1-cyclopropoxyimino)acetamidocou 4-fluoromethyl-2-okino1-azetidinesulfonic acid and (3S,4R+ -(-1-3-(( Z + -
2-(2-amine-4-thiazolyl)-2-(1-carboxine-1-cyclobutoximino)acetamide]=
The present invention was completed by newly synthesizing 4-fluoromethyl-2-oxo-1-azetidine sulfonic acid and discovering that these new compounds have extremely excellent antibacterial properties and are useful as pharmaceuticals. . That is, the compound 9 of the present invention is a compound represented by the above formula 13, (3S,4R)-(
-)-3-((Z) -2-(2-amino-4-thiazolyl+ -2-(1-carboxy-1-cyclopropoquinimino)acetamidocou 4-fluoromethyl-2-
Oxo-1-azetidine sulfonic acid and (38,4R
+-(-1-3-C(Z + -2-(2-amino-4
-thiazolyl)-2-(1-calhoki7-1-7croptoxyimino)acetamide"-4-fluoromethyl-2
- A pharmaceutically acceptable weir that has the optical activity of Okino 1-Azetidine Sulfone Reed is:
? 11) Alkali metal salts such as IJum salts and potassium salts: Alkaline earth metal salts such as Cal/Umum salts and Magne/Rum salts: Inorganic amine salts such as ammonium salts: Trimethylamine weir, triethylamine WIN, N-dibenzylethylene diamine salts, propionic acid, such as: hydrochloride, hydrobromide,
Inorganic acid salts such as sulfates, phosphates, nitrates; Organic acids such as acetate, lactate, propionate, maleate, malate, tartrate 1 citrate, methanesulfonate, isethionate. Salt: Examples include amino acid salts such as arginine salt, lysine salt, aspartate, and glutamate. Next, the method for producing the intermediate of the present invention will be described. The synthesis of (3S.4R)-(-)-3-t-butoxycarbonylamino-4-fluoromethyl-2-azetidinone [7], which is an important intermediate of the compound of the present invention, is L(-)-γ- Fluorothreonine (2) l:(
α) n 1 so (c=5, f-I201
) as a starting material + M, J, Mi Iler et al. (J, Am, Chem. Soc, 102, '7026 (19801
] According to the directions, they set out to join forces. L(-1-γ-fluorothreonine [2) was dissolved in dioxane to 2-t-butoxycarbonylthio-4,6-dimethylpyrimidine (hereinafter referred to as B
oc-8) was used to form t-butoxycarbonyl (hereinafter Boc (!: abbreviated), NBoc-γ-fluorothreonine C3] km, 6°N -Boc-r
-Fluorothreonine C3) High contact λal! in the presence of a condensing agent such as benzylhydroxylamine and N,N-dicyclohexyfluorcarposiimide (DCC)! i
or N-hydromushroom succinimide (H
O8u) or 1-hydroxybenztriazole (
Boc-γ- by reacting with HOBI I in the presence of DCC
After changing to active ester of fluorothreoni/, O-
Reaction with benzylhydroxylamine yields O-benzyl-N-Boc-r-fluorothreonine hydroxamate [4]. Hydroxamate [4] Hatriphenylhonuphine 1 is ring-closing reacted in the presence of Shigakikatan and triethylamine or in the presence of diethyl azodicarboxylate (DgADl and triphenylphosphine) (38,4几ノ(13-Boc-Amino-
1-benzyloxy-4-fluoromethyl-22〇-oquinoazetidine (5]'a-gives. [[α]. -44,5° (c=1, 0H301-th). [5]
Catalytic reduction of this in the presence of palladium on carbon yields 1-hydroxyazetidinone [6]. When l-hydroxyazetidinone [6] is reduced with titanium trichloride (38,
4R) (1-3-Boc-amino-4-fluoromethyl-2-oxoacetidine [7] is obtained.
[α:]D-1102°(c=1, (3I(30H
)]. C2][,3,] (4] (5,1 (63[7)) Next, the uninvented production method will be described.
] is used to synthesize as follows. [:7]yx Treatment with 1/fluoroacetic acid (3S. 41% 1-(-)-3-amino-4-fluoromethyl-
2-Oxoacetidine (gives 81. Compound

R in [9] is a carboxyl protecting group 1, e.g. t-
It means butyl or benzhydryl, and n means 22 and 3 digits. For example, (2)-2-12-to1) thylamino-4-thiazolyl)-2-(1-1-)゛toxycarbonyl-1-cyclopropoxyimino)acetic acid

[9]
is converted to acid chloride by the action of phosphorus pentachloride, and reacted with the azetidinone [8] in the presence of triethylamine to form (38,4l)-1-1-3-((Z)-2-( 2
-tritylamino-4-thiazolyl l-2-(1-t-
petitoxycarbonyl-1-cyclopropoxyimino)
Acetamidocou 4-fluoromethyl-2-oxoazetidine [10] is obtained. Compound (10) Sulfonated with pyridine-sulfuric anhydride in dimethylformamide (DMFI.!fcf12-picoline-sulfuric anhydride complex, (3S,4R1-(-)-3-[: (
z+-2-(2-)ritylamino-4-thiazolyl)-
2-(1-1-Butquinecarbonyl-1-cyclopropoxyimino)acetamidocou 4-fluoromethyl-2-
Oquino 1-azetidine sulfonic acid (11) is obtained. When compound [11] is treated with water-containing formic acid, trifluoroacetic acid, and a mixture thereof, not only the trityl amine protecting group but also the t-butyl protecting group of the carboxyl are removed (38,4R)-(- 1-3-((Z)-
2-(2-amine-4-thiazolyl l-2-(1-carboxy-1-cyclopropoxyimino)acetamide]-
Inner salt of 4-fluoromethyl-2-oxo-1-azetidinesulfonic acid [1]? Obtainable. This molecular inner salt is all suitable caustic alkali! j 'E When fc is neutralized with alkali carbonate etc. and freeze-dried, the target compound t with o=2 is obtained.
3s,4R)-(-1-3-C(Z)-2-(2-amino-4-thiazolyll-'2-(1-carboxy-
1-Shiklov. roboquiniminone acetamide-fluoromethyl-2
The potassium salt or sodium salt of -oxo-1-azetidinesulfonic acid (]l) is obtained.The same operation as above is performed to obtain the target compound of n = 3 (
3S, 4I(+-1-1-3-[: (Z) -2-
(2-amino-4-thiazolyl)-2-(1-carboxy-1-7 clobutoximino)acetamide-cow-fluoromethyl-2-oxo-1-azetidinesulfonic acid (
The potassium or sodium salt of 1) is obtained. [7] [8] Starting from intermediate [7], the 1st position of sult of azetidine
The target compound [1] can also be synthesized by first carrying out fluorination, forming a tetra-n-butyl-ammonium (hereinafter abbreviated as TBA) salt, and then carrying out acylation. Boc f trifluoroacetic acid (TFA) of the amine protecting group of intermediate [7]
J to convert to [8], and convert the amine group to benzyl oxy7 carbonyl fob t with penzylchlorophone remate.
), (33,4R1(-1-3-Cbz-amino-
He-fluoromethyl-2-oxoazetidine [xl] is obtained. (12) Ire pyridine-sulfuric anhydride primary is 2-
Sulfonated with picoline-sulfuric anhydride complex,
(38,4R)-t-1-3-Cbz-amino-4-
Fluoromethyl-2-oxo-1-azetidine sulfonic acid is isolated as the TBA salt [13]. [[α)D-12,1° (c = 1.02H50HI
]. [13] Catalytic reduction in the presence of Nihaladium carbon (33
,4l-(-1-3-amino-4-fluoromethyl-2-okino-1-azetidine sulfone [[TB A
Give salt (14). Compound

[9] 几お工BI n has the same meaning as above. For example, (Z)-2-(2-amino-
4-thiazolyl)-2-(1-1-butoxycarbonyl-1-cycloproboxifimino)acetic acid

An active ester of [9], for example, (9) is reacted with an active ester obtained from 1-hydroxybenztriazole (HOBt) in the presence of N,N'-dicyclohexylcarposiimide + DCCI to form (3S,4R)-( -)-3-((Z)
-2-(2-amino-46-thiazolyl l-2-(1-
1-Butoxycarbonyl-1-cycloproboxifimino)acetamide]-4-fluoromethyl-2-oxo-1
-Azetidine sulfonic acid TBA salt [15] is obtained. TBA salt [15] was treated with trifluorocholic acid-anisole, and trifluoroacetic acid was distilled off. The inner salt of the target compound [1] with Erin = 2 is obtained by treatment with an M organic solvent such as ethyl acetate. The inner salt can be converted to the potassium salt by treating with a suitable caustic alkali or alkali carbonate and freeze-drying. =-3 target compound (38,4R) -(-)-3-((Z+-2-(
2-Amino-4-thiazolyl)-2-(1-carboxy-1-cyclobutoximino)acetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid (
1) can be converted into the potassium salt or sodium sodium salt. [15] [14] [15] Next, a separate method for producing the intermediate will be described. Intermediate (13) HD, M, PI oyd et al. (J, O
rg, Chem, . It can also be synthesized from L-threonine of the formula, 176 (19B2+) according to the method for producing (3S. 4 Sl -3-Obz-amino-4-methyl-2-oxo-1-azetidinesulfonic acid TBAti.L(-)- R-fluorothreonine (2) is treated with pendyl chloroformate to form N-
Obz -L-γ-fluorothreonine (16) was converted into N-hydroxysuccinimide (HO8u) and N
, N'-dicyclohexylcarposiimide (DOC) was reacted to form an active ester, and treated with ammonia to form N-0bz-L-γ-fluorothreoninamide (17
) get '. Compound [17] Reacts methanesulfonyl chloride in nipyridine to convert it to N -Obz -Q-mesyl-L-γ-fluorothreoninamide [18], and then converts it into pyridine-sulfuric anhydride or 2-picoline-sulfuric anhydride complex. The sulfone of the amide (1
1 row, N-C! bz-〇-mesyl-L-γ-fluorothreonine (N-sulfo)amide TBA salt [19]
isolated as Compound (x9)t! Intermediate [13] can be obtained by ring closure in water-1,2-dichloroethane in the presence of potassium carbonate. (2) α6] [17] [18] [19] The antibacterial activity of the uninvented compound [1] is indicated as PlfMIC (minimum inhibitory concentration) K1. The test bacteria are all β-lactamase producing bacteria that react with known standard substances.The uninvented compound exhibits stronger antibacterial activity than azuthreonam against these strains, making it an excellent antibacterial agent. The inventive compounds are useful for the treatment and prevention of bacterial infections.The uninvented compounds are used in the prevention or treatment of bacterial infections, as well as their pharmaceutically acceptable salts.Uninvented compounds , or its salt alone, can be administered orally or parenterally in a dosage form suitable for administration in combination with a pharmaceutically acceptable carrier. Examples include tablets, capsules, granules, fine granules, powders, solutions, suspensions, emulsions, 70 tablets, elixirs, lemon powders, suppositories, etc. Furthermore, if necessary, the above-mentioned Dissolving liquids and auxiliary agents. Stabilizers, binders, wetting agents, lubricants, disintegrants, etc. For example, it is possible to add the commonly used TA 710 agent. For injections, injection distillation is usually used. Water, physiological saline.Prepared at the time of use with a solution such as Glucose Injection I, and may contain stabilizers such as methyl paraoxybenzoate and propyl paraoxybenzoate if necessary.Tablets, granules, fine granules, and capsules usually contain gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, milk mash, sugar, corn starch, carunium phosphate, phosphorus, magnesium stearate, Merck, polyethylene glycol, silica or sodium lauryl sulfate, etc. Liquid preparations usually include sorbitol syrup, methylcellulose, crucose, 1m syrup, gelatin 1-hydroxyethylcellulose, carboquine methylcellulose, aluminum stearate gel.Edible oil, lecithin, nrubitan monooleate.Gum arabic, J4 Peach oil, coconut oil, oily ester,
Conventional additives such as propylene glycol, ethyl alcohol, methyl p-hydroxybenzoate, propionic acid, rubic acid, etc. are used. Suppositories may also contain conventional suppository bases such as, for example, cacao butter 2fc and other glycerides. The dosage of the uninvented compound and its pharmaceutically acceptable salts varies depending on the patient's age, symptoms, and administration target, but is generally 1 to 100 grams per patient's body weight IK9, preferably 1 to 5 grams. ~301n9 is administered orally or parenterally in 2 to 4 divided doses per day. The uninvented compounds can be used as agents to treat or prevent bacterial infections, such as respiratory infections in mammals. It can be used to treat urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetric and gynecological infections, surgical infections, etc. Next is misfire 1. Among IIJ compounds: 81 manufactured IJ
(z Shown as a reference example. Reference example l. 0-benzyl-N-Boc-γ-fluorothreonine hydroxamate a) L-(-1-γ-fluorothreonine 1jJ ('
'129 mmol and triethylamine 1.5 mlV
(IQ9 mmol) was dissolved in 4 rnl of water. Boc-S 1.99 (a02mmolJ
f dioxane 4rnI! Dissolved in 7? The solution was stirred at room temperature for about 20 hours, then 11 drops of water was added to the reaction mixture, washed twice with 15 mL of ethyl acetate, and then 1 l of ethyl acetate was added. '(J layered, 6N1-IC)
Adjusted to H2. The ethyl acetate layer was separated and further extracted twice with 6d portions of ethyl acetate. After combining the ethyl acetate extracts and washing twice with 5% hydrochloric acid 7rrLt saturated with 9 chloride,
Drying over anhydrous sodium sulfate ram and evaporation to dryness under reduced pressure yielded the oily N-Boc-L-γ-fluorothreonine 193,9 ii. 6) 0-benzylhydroxylamine hydrochloride 232,
j9 (14.6 mmol)'l:, dissolved in water 64-. The pH was adjusted to 45 with 6N NaOH. In this solution, N-B
oc -L-γ-fluorothreonine L93. ! Add a solution of 9 in tetrahydrofuran (THF116).Next, keep the pH at 4.5 with 6N hydrochloric acid.N'-dicyclohexylcarposiimide (DCC)
jp (14.6 mmol) of THE'48-solution W- was added dropwise with stirring. l) Stirring was continued at 1, at which no fluctuations in H were observed, THF was evaporated under reduced pressure, and 80% of ethyl acetate was added. Insoluble N,N'-dicyclohexylurea was removed by filtration, and the ethyl acetate layer was separated, further extracted twice with 40 ml of ethyl acetate, placed on a 0.0 ethyl acetate extractor, dried over sodium sulfate, and dried under reduced pressure. The precipitated crystals were collected by filtration and washed with ether. Yield: 1.95g (L
-17a1% yield from r-fluorothreonine). To Ip122~E 23 °C IR, (KBrl: cm' 3350, 1665.1530.1370.1310.
1250.117ON HEIR (DMS Od6)
: δ in ppm143(91
(,s), 19-4.7 (4H, ml, 4.8
3 (2H, s l, a46 (LH. d, J=5Hzl, a45 (II-I, d, J
='15 Hzl, 743 (5H, sl. 11.28 [11-1, s 1 Reference example 2 (3S, 4 Rl-(-) -3-Boc-amino-1-benzylox/-4-fluoromethyl- 2-oxoazetidine al O-benzyl-N-BocT-fluorothreonine hydroxamate 146g (4.26mmol)k
Dissolve in 42 ml of anhydrous acetonitrile, add triphenylphosphine H53i9 (a54 mmol), carbon tetrachloride Q 54 ml (554 mmol) and triethylamine 054 ml (a4 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere F for about 18 hours. The reaction solution was concentrated under reduced pressure, subjected to silica gel furanone column chromatography, and n-hexane-ethyl acetate (
4:1), spasticity, and crystallization from inglobil ether (IPE) resulted in an IQ of 390.
(283%) of the title compound was obtained. M986
~87c [α) D-44,5° (cm1, CH3
0H) Elemental analysis value 0.6H2, FN204 Calculation ([: 0,59.25:H, a53:N, a64
Actual value: 0,59.32:H, a75:N, a'70
IR (KBr): cm'3330.1760.1'710, 1540.12B5
, 1170.995NM (DMSO-d61: δ
in pp”141 (9H,s) + 39=4
．． 4 (2H, m), 4.7 (2H, d d,
J=48&31-b l. 4.99 (2H,s), ″14B(51(Is)
,'! 67 (IH, d, J=7H2Jbl O-benzyl-N-Boc-r-7l, 1-.Threonine hydroxamate l'i! 15.j9(
5Q1 mmol) and triphenylphosphine 21 g (6
1 mmo I) in 4307 liters of anhydrous acetonitrile
VCM explanation. Diethyl azodicarboxylate (D
E A D ) 9.41tttl (6 liters 1 mmo
A solution of 1 liter of anhydrous acetonitrile at 20+pi was added dropwise over 20 minutes. After stirring at 15C for 4 hours, the reaction mixture was evaporated under positive pressure, separated by phosphoric gel flash force chromatography, and crystallized from IPE to give a78!9 (
417%) of the title compound was obtained. Reference Reli 3 (3S, 4 liters) -(-) -3-Boc-amino-4
-Fluoromethyl-2-oxoazetidine al (3
S, 4R,) (1-3-Boc-amino-
1-Benzyloxy-4-fluoromethyl-2-oxoazetidine l O9 (3Q8 mmol) was dissolved in methanol 5
00 hLl, 10% palladium on carbon-11 was added to the solution, and hydrogenation was carried out under high pressure for 2 hours. Directly use the catalyst and evaporate it under reduced pressure (38.4 liters) ()
3 sac -amino-4-fluoromethyl-1
-Hydroxy-2-oxoazetidine was added. b) For reference, 1-hydroxyazetidinone obtained with 1J Sal in 15 orrtl of methanol and 150 orrtl of water! n
1 of the bath solution was adjusted to 1) H7 with 10% caustic soda, and while keeping this solution at pH 7, 128 at of a 20% titanium trichloride aqueous solution was lowered to 1F4 over 2 hours at 10C. The mixture was further stirred for 2 hours. Aq the pH of the reaction solution to 8,
%N a O-6 bath g 600 rug and ethyl lactate 1
200id was added, insoluble materials were filtered off, and the organic layer was separated from the aqueous layer. The aqueous layer was further extracted with 600 d of ethyl acetate. The extracts were combined, dried over sodium sulfate, concentrated under reduced pressure, and the surface was washed with inglobil ether (IPg).
) to obtain 82 g of the title compound L (yield 271% from the l-benzyloxy compound). M9189-190C (deCl. [αID 11α2 (C-1, CI-■30FI)
Elemental analysis value C0H15FN203 Calculated value: 0,4Q54:H,a92:N,1284 fruit 61li) Ill: C,4a99:H,'Zoo
:N, 1256IR (KBr): cm-'32'70, l'i'60, 1750, 168
5, 1540, 1295, 1170, 1000
NMR (DMSO-d6): δ in ppm1.
39 (91-1, s), a3~4.0 (11
-1, m), 4.2 to 4.9 (3H, m),
'256(II-I, d, J=7Hzl, Q2(IH
,br sl Reference example 4゜(3S, 4IL) (-) -3-Cbz
-Amino-4-fluoromethyl-2-oxoazetidine (38,4 liters) I l -3-Boc-amino-4-fluoromethyl-2-oxoazetidine:! -0
9 (13.7 mmol) was dissolved in a 15 ml 1K bath of trifluorosoric acid cooled to OC, and the bath solution was stirred at the same temperature for 1 hour. The reaction solution was evaporated under reduced pressure, and benzene was added to the residue. It was evaporated and this operation was repeated twice. The residue was dissolved in ethyl acetate and the solution was heated at oC.
5 tnl of triethylamine was added, and then 2 J of pendyl chloroformate (1:!h 7 mmo
I was added under stirring. After stirring this 7tani solution for 2 hours, cold water was added. Take the ethyl trichloride layer and dehydrate with sodium sulfate. It shrunk with reduced pressure. The residue was purified by silica gel flash column chromatography using ethyl acetate-hexane ('7:3) and crystallized with isopropyl ether to obtain L.
8. The title compound of jil (52%) was obtained. Mp98
~1OOc. IL (KB r ): cm-1 32B0, 1760, 1745, 1690, 1
545, 1270, 1145. 1020.100O NMR (DMSlooON: δin ppmS7~4
．． 1 (lH, m), 4.2-4.9 (3H, m
), all (2H, s l, Q96(IH+
d + J==8Hz), Q6 (LH, s)
,'l 36 (5H, s) Reference Example 5 (3S, 4R) -() -3-Obz-amino-4-fluoromethyl-2-oxo-1-azetedi/sulfonic acid tetra-n-butylammonium salt (38,4 liters) () -3-C! bz-amino-
4-Fluoromethyl-2-oxoazetidine L 51
fl (6 mmol) of dimethylformamide (DMF
) 91 g (12 mmol) of pyridine-sulfuric anhydride complex was added to 20 mg bath solution and stirred at room temperature for 5 days. The reaction solution was poured into 300 tttl of cold 05M potassium phosphate bath solution adjusted to pH 5, washed three times with 100 tttl of methylene chloride, and diluted with tetra-n-butylammonium hydrogen sulfate ZO4,
9 (Q6 mmol) was added. This aqueous solution was extracted 4 times with 100 m/m of methylene chloride, and the extract was 8%
Wash with saline, dehydrate with sodium sulfate, and add 1 ml.
The precipitated crystals were collected by filtration with the addition of ethyl acetate to obtain the title compound 2.5. ! 7 (73 chi) was obtained. MpH3-11
5C. [α:] D-1216 (C = 1.021-1,081 elemental analysis value C28H48N3FO6S measurement value: C
,5a61:H,843:N,'132 real fflli l
Straight: 0.5a43:H, Q79:N14011"
tlKI)r), cm 1765 , 1720 , 1530 , 12B0 , 1
135, 104ONl'Vl 几 (1) MSO (
+6)' δ i'n ppm
Q95 (121-1, t, J=a51-1z)
, 1. ICr-L80 (161-1, m),
S05~340 (8H, ml, Q93 (1N +
ml, 4.53 (IH, d, J=871-1z
l, 4.72 (21-1, dd, J=42&2[
-1z) , Q08 (2H, s l +q40
(5H, si. 805 (11-1, d, J=a71-1z) Reference example G N -Obz -L-γ-fluorothreoninamide a
)L(-)-γ-fluorothreonine 137g (α1m
ol) and triethylamine 2Q9d (Q15 mol) in a 50% dimethylformamide (DMF) water bath, and while keeping the temperature at 5 to 10°C, pendyl chloroformate 2L6-(Q15 mol)'i was added dropwise under stirring. After stirring at the same temperature for 1 hour, the reaction mixture was poured into 350 mA of ice water and washed with 200 mA' of ethyl acetate. The aqueous layer was purified with 6N hydrochloric acid.
Adjust to H25. Extraction with ethyl acetate, dehydration over anhydrous sodium sulfate, and concentration under reduced pressure yielded 251'7 g (95%) of oily N -Obz -L-γ-fluorothreonine. 4%t. b) N-Cbz-L-r-fluorothreonine 2'21 g (α1 mol) and N-hydroxysuccinimide (HO8u) lal, ji' (Q
llmol) of tetrahydrofuran (THF) 20
N, N'-dicyclohexylcarposiimide (DC!0) 216,9 (α105 mol
)i was added, and after stirring at room temperature for 2 hours, 7tN was precipitated.
, N'-dicyclohexyl urea was separated from the source, 2N solution was ice-cooled, 75N ammonia water 32 me and T I-IF
The mixture was added to 32 ml of bath solution and stirred for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was dissolved in ethyl.
After washing with an aqueous solution of sodium hydrogen carbonate and a saturated saline solution and evaporating the ethyl chloride under reduced pressure, the precipitated crystals were washed with a small amount of ethyl acetate to obtain the title compound 9, 212'?
(Achieved 90%l. Mp 141~145r
[α]D + 9. 4° (c=
l, C2H50Hl■几(KBr l: cm
"3420, 3310.3220, 1690, 16
40, 1535, 020. 1300.1250, 1060, 1015.870.6
95NMR (DMSO-d6): δin ppm4.0
=4.30(31-1,m,l,4.60(IH+m
), 50B(2H,sl, a40(IH,d, J
=5Hz), ass (II-1, d, J=8H2)
, '220 (lH, br-s). 73th edition 0 (61-1,51 Reference example 7 N -Ob z -0-mesyl-L-γ-fluorothreoninamide N -Cb z -L-γ-fluorothreoninamide C36,9 (13 mmol f anhydrous pyridine 13 'r
Methanesulfonyl chloride L 2 rnl (1a3 mmol) was added dropwise to a double bath with stirring at 5C or less, and stirring was continued at that temperature for 2 hours.The reaction solution was added to 120 ml
! After stirring for 30 minutes, the precipitated crystals were collected by filtration to obtain the title compound a79. ! I got 9 (8a7ch). Engineering R (KBr); crn-13430,3
320, 1670, 1620, 1535, 1350, 1
250, 11B5. 1070.1050.970.930.820. '7
50.695NMR (DMSO-a6+: δin p
pm516 (3H, sl, 4.60 (LH, d
d, J=9&5[(z), 4.70(2t1.d
d. J=5&a7Hz l, 4. g a2 (3H, m)
, 'Z yari 50 (6H, m). 755 panic 80 (2H, m) Reference example a N -cb z -0-mesyl-L-γ-fluorothreonine (N-sulfo]amide tetra n-butylammonium salt 2-picoline a84m/methylene chloride 451I
299 ml of chlorosulfonic acid was added dropwise to the Le solution while stirring while cooling with water and keeping the temperature below 5 c. This bath solution was mixed with methylene chloride 6 of N -Obz -0-mesyl-L-γ-fluorothreoninamide 379I.
After adding 0 ml of suspension and boiling under reflux for 16 hours, the reaction mixture was cooled and poured into 30 ozg of (15M +77 acid-sodium solution (1)) (4,5). The aqueous layer was separated, and tetra-n-butylammonium hydrogen sulfate (aosyl) was added to the aqueous layer, and the solution was extracted twice with 7ffl of methylene chloride (4d).The extract was evaporated to dryness under reduced pressure to obtain the title compound 9. Obtained 565 g (74%) as a foamy solid. NM几(DMSO-d6): δin ppmQ941
121-1, L, J=a21-1z),
Ll-L8 (16H, ml, aolr-a50(
I II (1rn), 4.50 (LH, rn),
4.52 (2H+ d d , J=475&X7Hz
l +50 thirst 30 (31-1, ml, 73Ch
-'! 50 (6H, s l, Q96 (IH, b
r s J reference example 9゜(38,4R) () 3-Cbz-amino-4
- Fluoromethyl-2-oxo-1-azetidine sulfone tetra-n-butylammonium N in a mixture of boiling refluxing potassium carbonate aog, water 72 ml and 1,2-dichloroethane 5B, ME
-Ob z -0-Mesyl-L-γ-fluorothreonine (N-sulfo)amide tetra-n-butylammonium salt 1'159 (!SL6 mm 1,2-dichloroethane 9 At bath solution added and boiled for 20 minutes After refluxing, the reaction mixture was cooled, methylene chloride was added thereto, the organic layer was separated and evaporated under reduced pressure to obtain an oily residue. Subjected to silica gel flash column chromatography,
Collect the fractions that do not contain the target substance. Concentrate under reduced pressure to obtain a crystalline residue and wash with a small amount of ethyl acetate to obtain the title compound. Ia 51 ji (159 section)
I passed. Production examples of the present invention will be shown below as examples. Example 1 (38,4R)-(-)-3-C(Z)-2-(
2-amino-4-thiazolyl)-2-(1-carboxy-1-cyclopropoxyimino)acetamide]-4-
Fluoromethyl-2-oxo-1-azetidinesulfonic acid reference? 11! Compound 1.38.9 (24m
mollt7) N,N-dimethylformamide 501t
tl solution fi in the presence of 400 m2 of 10% palladium on carbon for 2 hours at room temperature III! l! I made a reduction. After separating the catalyst. (Z)-2-F2-amino-4-thiazolyl)-2-(
1-1-Butoxycarbonyl-1-cyclopropoxyiminol DIR7907ny (24 mmol. l-Hydroxybenzotriazole 360 my(26
4 mmol and N,N'-dicyclohexylcarbodiimide 520''9 (24'mmol f) were added. The mixture was kept at room temperature for 20 hours. The reaction solution was evaporated to dryness under reduced pressure, and methylene chloride was added to the solution to remove insoluble matter. 71
・As a gift, acetone-methylene chloride (45:a5
Using silica gel flats/Yukalam chromatography to make a branch using J', anisole 24
．． Take the blade and heat it to -15C! -1J L, 14.4 nLl of city trifluorosoric acid at Kaloe IOC 2
Time was in full swing. Added 5 ornl of ethyl to the reaction solution! and methanol 10 rttl k and approx. 5 rn under reduced pressure.
l'? Concentrate and add 30 rIL of ethyl acetate to the concentrated liquid.
was added and the insoluble matter was filtered off. After stirring this material in 5 rttl of 95% ethanol for 30 minutes, 5 rttl of methyl 1/7 chloride was added and stirred for an additional 30 minutes. The precipitate was collected by filtration to obtain 390 ml of the title compound (yield: 36%). Mp 164C (dec, 1 [α)D 27° (c = 1 + 82011R
(KBr): cm 1'750, 1670, 1630, 1570,
1250, 1240, 1200, 10105ON
(DMSO-d6J: δin ppmh3-L5
(4H, m), S'7~41 (IH, m7, 4
．． 3~al (3H, ml."21(LH+s), C45(IHld 1J=
=81-Iz) Elemental analysis value C13H14FN508
S2 calculated value: 0, 34.59:H, 113:N, 1a
51: S, i, 21 actual measurement value: C, 34, 25: H, 2
98:N, 1a29:S, 14.30 Example 2 (38,4R)-(-)-3-C(Z)-2-(2
-amino-4-thiazolyl) -2-(1-carpoki/
14.9 g (26 mmoi
i N,N-dimethylformamide 100me common enemy 1
Catalytic reduction of gold was carried out at room temperature for 2 hours in the presence of 4.5 g of zero-coupling palladium on carbon. After filtering off the catalyst, (z + 2 72
-amino-4-thiazolyl) -2-+ 1-t-butoxycarbonyl-1-cyclopropoxyimino I If
a 51.5' (26mmol, l-hydroxybenzotriazole 5B 6,9 (2a6mma
ll and N,N'-dicyclohexylpodiimide a-36jl (26 mmol) were added to the river and subjected to the same reaction at room temperature for 20 hours. Reaction g was evaporated to dryness, and methylene chloride was added to the residue 6j to remove the unbaked product. 2. Separate the decoy using acetone-methylene chloride (4,5:a5) using silica gel flash column chromatography, and add 25 tL of methylene chloride to the obtained solid.
+ani7-ru13,ue'f/JIIe,1
5rV-cool and add I-cold trifluoroacetic acid 757a.
The mixture was stirred at C for 2 hours. Add 300 ml of ethyl sulfate to the reaction solution.
Then add 100 ntg of methanol and boil for about 30 ntg under reduced pressure.
Condense c4 with ntg 1 and add ethyl 20 O to the concentrate.
ntl was added and insoluble matter was filtered off to obtain 9.05 g of crude powder. The mother liquor and wash liquor were condensed and I! rIl: Ethyl acid was added and insoluble matter was filtered off to obtain an additional 097 g. The above coarse powder 10.9 was dissolved in water at 100/LIVc, and 6
After adding N-hydrochloric acid α5 rttl, 3 tons of water, 2 tons of 5% methanol water, and 51 tons of 15% methanol water were poured into the Mitsubishi Diaion HP-20 (l 1. l).
The entire fraction containing the objective'm. After removing methanol under reduced pressure, it was lyophilized to obtain the title compound 71 ojq (yield: 60 q) as a powder. (B) The above powder was added dropwise to 5 ml of water, and all 43 streams of isopropyl alcohol were added dropwise. Crystallize and collect by filtration to obtain toingrovir alcoholate 728 of the title compound.
．． I got a 9. Mp 158r (dec, 1 [α)2. . 14° (C=1 total 120) T R (K
I3 r ): cm17'7 (1,
1685, 1625, 156 ('T, 1250,
1230, 1104ON (DMSO-d61:
δ in ppm1.07 (6N, (1, J=
=61-IZl, 1.3-1.5 (4H, ml,
:! , 6-4.1 (21-1, ml. a, 3-al L30, m), '205 (111
, s l, 9.42 (LH, d, J=8tlz
) Elemental analysis value CI6■■2゜Ii'N50. S2 calculation (direct: 0.3'!57:II, 4.34:N,
1169:S, 12.54 Actual value: 0.3'! 20:
II, 4.16:N, 1593:S, 1287(C) 328g of the above toinopropyl alcohol per day and 30+++J of acetone! After stirring at 50'C for 20 minutes, the mixture was cooled, stirred for an additional hour, and filtered to obtain 2.85 g of the title compound. Mp 164°c (dec,) [α]D-27° (C=1.K20) I R (K B
r l , N M R (D M S Od s l
: Same elemental analysis value as the compound obtained in Example 1 013F■, 4FN508S2c+tx value: C, 34, 59: I-1, 113: N, 1a51:
S, around 14.21 actual measurement: Ci, 34.74:H, a2
8:Nja06:S, 1a94 Example 3 (3S, 4R) -1-1-3-C(Z) -2-
Potassium (2-amino-4-thiazolylj-2-11-carboquine-1-cyclobutoxy)iminoacetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonate Compound obtained in Reference Example 5 531 nl (L 1 mmol
l of dimethylformamide 20 WLe % p k
Catalytic reduction was carried out at room temperature for 2 hours in the presence of 1 g of 10% radium on carbon. After filtering off the catalyst, (2
1-2-(2-amino-4-thiazolyl)-2-(1-
Diphenylmethoxycarbonyl-1-cyclobutoxyimino) last fi 497 W (L 1 mmall. l-Hydroxybenzotriazole 164 my (L
2mmol and N,N'-dicyclohexyllupodiimide 22'l''51 (Llmmol f
The mixture was added and stirred at room temperature for 20 hours. The reaction solution was evaporated to dryness under reduced pressure, methylene chloride was added to the residue, insoluble matter was filtered off, and acetone-methylene chloride (45:a5
1'i was used for separation and purification by silica gel 7 lattice column chromatography.
πl! was added, cooled to -15C, 126 ml of cold trifluoroacetic acid was added, and the mixture was stirred at OC for 15 minutes. 50rt113 of ethyl acetate and 113 ml of methanol were added to the reaction solution, and the mixture was heated under reduced pressure to remove 30 me of ethyl acetate. This material was suspended in 20 liters of water, and the suspension was adjusted to a point of 16 with 05N aqueous potassium hydroxide solution and freeze-dried. After dissolving this wJ in a small amount of water, Diaion LIP-20 (25n
tl) and take a bath with water. Collect the fraction containing the 4th omega and freeze-dry it. The title compound 180g (yield 3a2%) was obtained. Mp 164C(dec,) [α]U-150° (C=1.lI20)1)t
(K13 r l: cIn-'177Q, 166
0.15B5, 1535, 1395.1270.124
5゜1205.11'70.1120.105ON M
几(Dl'v[5O-d61: δ
in ppm1.6-25 (61-1,ml,
S8~4.2 (it-1, ml, 4°3~a2 (
31(, ml.

Claims (1)

[Claims] 1) An optically active compound represented by the general formula ▲A mathematical formula, a chemical formula, a table, etc.▼ (wherein n means 2 and 3) and a pharmaceutically acceptable salt thereof. 2) (3S,4R)-(-)-3-[(Z)-2-(2
-amino-4-thiazolyl)-2-(1-carboxy-
The compound according to claim 1, which is 1-cyclopropoxyimino)acetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid. 3) (3S,4R)-(-)-3-[(Z)-2-(2
-amino-4-thiazolyl)-2-(1-carboxy-
The compound according to claim 1, which is 1-cycloptoxyimino)acetamide]-4-fluoromethyl-2-oxo-1-azetidinesulfonic acid.