A practical and facile synthesis of azetidine derivatives for oral carbapenem, L-084

Article abstract of DOI:10.1248/cpb.54.1408

An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1β-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.

Full text of DOI:10.1248/cpb.54.1408

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1408
Chem. Pharm. Bull. 54(10) 1408—1411 (2006)
Vol. 54, No. 10
A Practical and Facile Synthesis of Azetidine Derivatives for Oral
Carbapenem, L-084
b
Takeshi ISODA,*,a Itsuki YAMAMURA,a Satoshi TAMAI,a Toshio KUMAGAI,a and Yoshimitsu NAGAO
a Medical Research Laboratories, Wyeth K.K.; Kashiwa-cho, Shiki, Saitama 353–8511, Japan: and b Graduate School of
Pharmaceutical Sciences, The University of Tokushima; Sho-machi, Tokushima 770–8505, Japan.
Received June 14, 2006; accepted July 27, 2006; published online August 7, 2006
An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-
yl)azetidin-3-ylthio moiety at the C-2 position of the 1b-methylcarbapenem skeleton. We established a practical
and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of
L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-
hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.
Key words L-084; carbapenem; azetidine; Bunte salt
Carbapenem antibiotics have long been in the spotlight be-
In this paper, we describe a practical and facile synthesis
cause of their potent antimicrobial activity. The attention of of thiol 1 via Bunte salts 19 and 20 as key intermediates.
both academic and industrial scientists has been attracted to This synthesis method for 1 is amenable to large-scale pro-
the development of a new carbapenem for clinical use. Since duction.
imipenem1) was launched in 1987 by Merck Co., five addi-
Optimization of the Reaction for Azetidine Ring-Clo-
tional compounds, panipenem,2) meropenem,3) biapenem,4) sure30) We have previously established the synthesis of
ertapenem5) and doripenem,6) are now on the market. How- 1 through 3-hydroxyazetidine hydrochloride (5) as a key
ever, all these were developed for parenteral use, and the de- intermediate.28) Compound 5 was obtained in two steps
velopment of carbapenems for oral use has been expected for including cyclization of N-benzhydryl-3-chloro-2-hydroxy-
a long time. The title compound L-084 is one of the hopeful propylamine (3) and deprotection of the N-substituent
candidates among recently reported oral carbapenems such according to the literature (Chart 2).31,32) Although compound
as CS-834,7—12) GV-11881913—17) and DZ-2640.18—27) L-084, 5 has been well recognized as a useful building block for
an ester-type prodrug of the active metabolite LJC11,036 (2), various bioactive molecules such as antimicrobial agent
shows high bioavailability in humans,28) and exhibits high WQ-2743,33) antiepileptic Dezinamide34) and antihyperten-
antimicrobial activity against Gram-positive and Gram-nega- sive Azelnidipine,35) it has been suggested that the above
tive bacteria.29) The structural feature of L-084 is an achiral two-step procedure for 5 was too expensive to adopt for
azetidine moiety at the C-2 position of the 1b-methylcarba- large-scale production. Therefore, we decided to develop an
penem skeleton, whereas CS-834 and DZ-2640 have a chiral alternative synthetic method for 5.
pyrrolidine moiety as shown in Chart 1. Synthesis of
In the reaction of an azetidine ring-closure, one or more
L-084 was carried out according to our reported procedure bulky substituents on the precursor were considered to be
(Chart 2).28) The condensation of enolphosphate 11 and thiol necessary to obtain the corresponding azetidine derivative ef-
1 afforded the p-nitrobenzyl (PNB) ester 12, which was then fectively. A practical method for the scale-up production of
subjected to hydrogenolysis followed by esterification with derivatives of azetidinols bearing a less bulky substituent has
pivaloyloxymethylchloride (POMCl) to give L-084.
not been developed yet.31,36—40) Regarding the preparation of
Chart 1
Chart 2
∗ To whom correspondence should be addressed. e-mail: isoda@konicaminolta.jp
© 2006 Pharmaceutical Society of Japan

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October 2006
1409
a less bulky N-benzyl derivative,41,42) only the O-protected group using a metal acylthiolate is one of the general method
compound 14 has been obtained by cyclization of 13 in low for the synthesis of various thiols and related compounds. In
yield (Entry 1 in Table 1). In order to provide an industry- the early stage of the development of L-084, thiol 1 was pre-
oriented reaction of azetidine ring-closure, we focused on N- pared from the acetylthio compound 9 according to the above
benzyl-3-chloro-2-hydroxypropylamine (15) as a precursor method we previously reported.28) As for a large-scale pro-
of the azetidine derivative 16, because 15 was prepared from duction, the oily compound 9 was considered not to be an ap-
benzylamine which was less expensive than benzhydryl- propriate precursor, and the second generation precursor,
amine. We initially checked out whether the benzylamino crystalline compound 10, was omitted due to the cost of a
group attacked the C-1 position of 15 under the same condi- metal thiobenzoate (Chart 2). As a more convenient method
tions of Entry 1, but the azetidine derivative 16 was not ob- for the preparation of 1, the introduction of a dithiosulfonate
tained at all (Entry 2 in Table 1). Because we had to avoid group was investigated. A variety type of alkylthiosulfate
using a protecting reagent as much as we could from the cost compounds, so-called Bunte salt,48) were known to be readily
point of view, we carefully carried out the optimization of re- prepared using economical sodium thiosulfate (Na2S2O3).
action conditions to obtain 16 from 15 in the 10 mmol scale However, probably due to its high polarity and poor solubil-
experiments summarized in Table 1. The yield was found to ity in organic solvents, there have been few applications uti-
be critically dependent on the solvent. The reaction pro- lizing this functionalized intermediate for a large-scale syn-
ceeded in 2-propanol (i-PrOH) or tert-butyl alcohol (t- thesis. Bunte salt 20, the precursor of 1, was successfully ob-
BuOH) in the presence of triethylamine (Et3N) (Entries 3 and tained from N-benzyl-3-hydroxyazetidine (16) in 4 steps.
4 in Table 1). Moreover, the yield of 16 dramatically in- Mesylation of 16 followed by hydrogenolysis gave rise to 3-
creased in acetonitrile (MeCN) when potassium hydrogen- methanesufonyloxyazetidine hydrochloride (18), which was
carbonate (KHCO3) was added as a base (Entry 8 vs. 2 in easily converted to Bunte salt 19 in 52% yield after stirring
Table 1). Finally, we could set the best reaction condition in with Na2S2O3 at 50 °C in methanol and water. The condensa-
which 16 was obtained in 90% yield (Entry 10 in Table 1). tion of 19 and 2-methylthio-2-thiazoline (7) afforded 20 in
We then examined the reaction on a 250 mmol scale under 67% yield. Although the two sequential reactions from 18 to
the optimal conditions, but the yield of 16 decreased to 73%. 20 both proceeded in moderate yield, we envisioned that the
In searching for the reason of less reproducibility, we found reactions could also proceed in a one-pot manner in a mixed
that the particle size of KHCO3 affected the yield of this re-
action (Table 2). Commercially available KHCO3 was con-
sidered not to be an appropriate reagent because of its wide
distribution range of particle size, whereas sodium hydrogen-
carbonate (NaHCO3) showed a narrow distribution range. We
demonstrated that the large particles contained in the com-
mercial reagent caused the decreasing of the yield. So we in-
vestigated the use of NaHCO3 instead of KHCO3 and con-
firmed that NaHCO3 was also a good reagent for this cycliza-
tion reaction (Entry 6 in Table 2). Further scale-up produc-
tion was accomplished with excellent reproducibility (Entry
11 in Table 1). Through these experiments, we established
the optimization of the reaction for azetidine ring-closure
that was useful and applicable to the manufacturing of 16.
Conversion of OH Group on Hydroxyazetidine Deriva-
tives to SH Group43—47) The introduction of an acylthio
Table 2. Effect of the Particle Size of KHCO3 and NaHCO3
Distribution
Reaction
Entry
Base
Particle size (mm)
ratio (%)a)
yield (%)b)
1
2
3
4
5
6
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
NaHCO3
335—500
250—355
177—250
150—177
ꢀ150
53.5
14.8
13.0
3.3
15.4
96.9
58
54
98
97
97
98
ꢀ250
a) Distribution ratio in commercially available materials. b) HPLC yield.
Table 1. Optimization of the Reaction Conditions for Azetidine Ring-Closure
Entry
Substrate
Solvent
Conc. (mol/l)
Base (eq)
Product
Yield (%)a)
1b)
2
3
4
5
6
7
8
9
1341)
15
15
15
15
15
15
15
15
15
15
MeCN
MeCN
t-BuOH
i-PrOH
i-PrOH
i-PrOH
t-BuOH
MeCN
t-BuOH
MeCN
MeCN
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
0.5
Et3N (3)
Et3N (2)
Et3N (2)
Et3N (2)
1441)
16
16
16
16
16
16
16
16
16
16
38
N.Rc)
70
60
—
N.R.c)
40
KHCO3 (2)
KHCO3 (2)
KHCO3 (2)
KHCO3 (2)
KHCO3 (2)
NaHCO3 (2)
57
58
85
90
10
11d)
93
a) Isolated yield. b) Refluxed for 3 d. c) No reaction. d) 3.2 mol scale.

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1410
Vol. 54, No. 10
Chart 3
C10H15ClNO: 200.0842). MS m/z: 200 (MꢃꢃH). Anal. Calcd for
C10H14ClNO: C, 60.15; H, 7.07; N, 7.01. Found: C, 60.12; H, 7.03; N, 6.98.
N-Benzyl-3-hydroxyazetidine (16) (Entry 11 in Table 1) A mixture of
15 (643.7 g, 3.22 mol) and NaHCO3 (542.0 g, 6.45 mol) in MeCN (6.4 l) was
refluxed for 7 h and allowed to cool to room temperature. The reaction mix-
ture was filtered, and the filtrate was evaporated to 600 g. To the residue were
solvent of methanol and water. After removal of the catalysts
in the hydrogenolysis of 17, to the resulting solution of 18
was successively added Na2S2O3 at 50 °C and 7 under reflux.
Unexpectedly, the overall yield of 20 in a one-pot manner
was disappointingly low (42% yield from 17). The reason of
the low yield of 20 might be due to the severe reaction condi- added AcOEt (300 ml) and heptane (3200 ml), and the mixture was stirred
for 1 h at room temperature. The resulting precipitate was filtered and dried
tion for the reaction of 19 with 7 (reflux, 17 h). As shown in
Chart 3, the use of chloroethylisothiocyanate instead of 7 en-
abled the reaction to proceed under mild conditions, and the
overall yield from 17 to 20 was improved (82% yield without
isolation of 18 and 19).
in vacuo to obtain 16 as colorless crystals (488.1 g, 93%), mp 64—65 °C.
1H-NMR (CDCl3) d: 2.93—2.97 (2H, m), 3.59—3.63 (4H, m), 4.39—4.45
(1H, m), 7.23—7.33 (5H, m). IR (KBr) cmꢂ1: 2837, 1496, 1476, 1453,
1342, 1174, 1083, 949. EI-MS m/z: 163.0997 (Calcd for C10H14NO:
163.1025). MS m/z: 163 (MꢃꢂCl).
3-Benzoylthio-1-(1,3-thiazolin-2-yl)azetidine hydrochloride (10) To
the warmed AcOn-Bu (20 ml) were added 3-methanesulfonyloxy-1-(1,3-
thiazolin-2-yl)azetidine (8)28) (2.36 g, 10.0 mmol) and potassium thioben-
zoate (2.64 g, 15.0 mmol) under stirring. After being refluxed for 5.5 h, the
reaction mixture was cooled to room tempreture, and 5% aqueous KHCO3
(7 ml) was added. The organic layer was separated, dried over MgSO4 and
filtered. To the filtrate was added 4 mol/l HCl in dioxane (2.5 ml, 10 mmol)
at 15 °C, and the mixture was stirred for 1 h at 10 °C. The resulting precipi-
tate was filtered and dried in vacuo to obtain 10 as colorless crystals (2.70 g,
Deprotection of 20 was carried out to obtain 1 by acid hy-
drolysis with conc. HCl.47) However, disulfide 21 concomi-
tantly formed in 10% yield and could not be separated from
crude 1. In order to obtain pure 1, we quitted studying the di-
rect conversion and tried to add an oxidation step. The result-
ing crude 1 was treated with hydrogen peroxide to afford 21
in quantitative yield as illustrated in Chart 3. Reduction of 21
with triphenylphosphine also proceeded quantitatively, and
thiol 1 was obtained in crystalline form, which was suitable
for use in the synthesis of L-084.
1
86%), mp 166—167 °C. H-NMR (CDCl3) d: 3.58 (2H, t, Jꢁ7.6 Hz), 4.15
(2H, t, Jꢁ7.6 Hz), 4.20—4.25 (1H, m), 4.52—4.60 (1H, m), 4.81—4.87
(2H, m), 5.23—5.31 (1H, m), 7.46—7.52 (2H, m), 7.60—7.67 (1H, m),
7.88—7.91 (2H, m). IR (KBr) cmꢂ1: 3443, 2980, 1656, 1446, 1305, 1208,
912. FAB-MS m/z: 279.0642 (Calcd for C13H15N2OS2: 279.0626). MS m/z:
279 (MꢃꢂCl).
Conclusion
We accomplished the synthesis of 3-mercapto-1-(1,3-thia-
N-Benzyl-3-methanesulfonyloxyazetidine hydrochloride (17) A mix-
zolin-2-yl)azetidine (1) in 52% overall yield starting from ture of 15 (225 g, 1.13 mol) and NaHCO3 (189.3 g, 2.26 mol) in MeCN
(2.25 l) was refluxed for 6.5 h, and the solvent including water was then re-
moved under reduced pressure to yield the residual solution of 16 (917 g).
After adding MeCN (1.24 l) and Et3N (140.5 g, 1.40 mol) to the solution,
methanesulfonyl chloride (140.0 g, 1.22 mol) was added dropwise over 7 h
benzylamine and epichlorohydrin. The new synthesis method
not only increases the yield but also reduces the cost by half
and is amenable to large-scale production. The reaction of
azetidine ring-closure was achieved even in the case of a less
bulky precursor 15 to afford 16 in quantitative yield. Com-
pound 16 was eventually converted to 1 via zwitterionic
Bunte salt 20 without isolation of 18 and 19.
under 5 °C. The reaction was quenched with 13% HCl in MeCN (359 g,
1.3 mol) under 5 °C, and the resulting precipitate was filtered and dried in
vacuo to obtain 17 as colorless crystals (245.6 g, 80%), mp 137—138 °C.
1H-NMR (CD3OD) d: 3.21 (3H, s), 4.33—4.65 (4H, m), 4.82 (2H, s),
5.36—5.39 (1H, m), 7.48 (5H, m). IR (KBr) cmꢂ1: 2986, 2507, 2454, 1351,
1169. FAB-MS m/z: 242.0849 (Calcd for C11H16NO3S: 242.0851). MS m/z:
242 (MꢃꢂCl). Anal. Calcd for C11H16ClNO3S: C, 47.56; H, 5.81; N, 5.04.
Found: C, 47.66; H, 5.82; N, 5.03.
3-Methanesulfonyloxyazetidine hydrochloride (18) To a solution of
17 (55.5 g, 200 mmol), MeOH (320 ml) and water (80 ml) was added 10%
Pd–C (0.56 g, dry reduced), and the mixture was stirred vigorously for 20 h
under 400 kPa pressure of hydrogen at room temperature. The catalyst was
removed by filtration, and the filtrate was concentrated and triturated with
MeOH–THF (15 ml : 45 ml). The resulting precipitate was filtered and dried
in vacuo to obtain 18 as colorless crystals (35.8 g, 95%), mp 106—107 °C.
1H-NMR (CD3OD) d: 3.11 (3H, s), 4.28—4.32 (2H, m), 4.49—4.54 (2H,
m), 5.41—5.47 (1H, m). IR (KBr) cmꢂ1: 2985, 1575, 1354, 1174, 1064.
FAB-MS m/z: 152.0378 (Calcd for C4H10NO3S: 152.0381). MS m/z: 152
(MꢃꢂCl).
Experimental
Melting points were determined using Yanagimoto micromelting point ap-
paratus. NMR spectra were obtained on JEOL JNM-EX270 (270 MHz) or
Bruker Avance DPX400 (400 MHz) spectrometers using tetramethylsilane
(TMS) or sodium 3-(trimethylsilyl)propionate-d4 (TSP) as an internal stan-
dard. IR spectra were recorded on a JASCO FT-IR (VALOR-III) spectro-
meter. Mass spectra were recorded on JEOL JMS-DX300 or JMS-SX102A
spectrometers. Elemental analysis was recorded on a Yanako CHN-Corder.
N-Benzyl-3-chloro-2-hydroxypropylamine (15) To a solution of benzyl-
amine (138.8 g, 1.58 mol) in water (1.5 l) was added epichlorohydrin
(138.8 g, 1.50 mol) at 5 °C, and the reaction mixture was stirred for 18 h at
15 °C. n-Hexane and i-PrOH (1 : 15, 300 ml) were added to the reaction mix-
ture, and the mixture was stirred for 2 h at 15 °C. The resulting precipitate
was filtered and dried in vacuo to obtain 15 as colorless crystals (265.2 g,
Azetidin-3-ylthiosulfonic acid (19) To a suspension of 18 (7.5 g,
40 mmol), MeOH (64 ml) and water (16 ml) was added Na2S2O3·5H2O
(10.0 g, 40 mmol), and the mixture was stirred for 20 h at 50 °C and then
cooled to room temperature. The resulting precipitate was filtered and dried
in vacuo to obtain 19 as colorless crystals (3.52 g, 52%), mp 225 °C (dec.).
1
89%), mp 72—73 °C. H-NMR (CDCl3) d: 2.72 (1H, dd, Jꢁ7.8, 12.4 Hz),
2.84 (1H, dd, Jꢁ4.1, 12.4 Hz), 3.56 (2H, d, Jꢁ5.6 Hz), 3.81 (2H, d,
Jꢁ2.0 Hz), 3.84—3.92 (1H, m), 7.23—7.37 (5H, m). IR (KBr) cmꢂ1: 3292,
2899, 1453, 1346, 1252, 1072, 882. FAB-MS m/z: 200.0833 (Calcd for

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October 2006
1411
1H-NMR (D2O) d: 4.19—4.27 (2H, m), 4.44—4.54 (3H, m). IR (KBr)
cmꢂ1: 3230, 1556, 1308, 1193, 1029. FAB-MS m/z: 169.9932 (Calcd for
12) Maeda K., Inukai M., Jpn. Patent JP10165195 (1998) [Chem. Abstr.,
129, 121709 (1998)].
C3H8NO3S2: 169.9946). MS m/z: 170 (MꢃꢃH). Anal. Calcd for C3H7NO3S2: 13) Gaviraghi G., Eur. J. Med. Chem., 30 (Suppl.), 467s—478s (1995).
C, 21.29; H, 4.17; N, 8.28. Found: C, 21.25; H, 4.08; N, 8.12.
[1-(1,3-Thiazolin-2-yl)azetidin-3-yl]thiosulfonic Acid (20) a) To a
14) Rossi T., Biondi S., Contini S., Thomas R. J., Marchioro C., J. Am.
Chem. Soc., 117, 9604—9605 (1995).
suspension of 19 (1.69 g, 10 mmol), MeOH (16 ml) and water (4 ml) was 15) Carlesso R., Holman S., Perboni A., Rossi T., WO9405666 (1994)
added 2-methylthio-2-thiazoline (1.60 g, 10 mmol), and the mixture was re- [Chem. Abstr., 121, 57223 (1994)].
fluxed for 17 h and then cooled to room temperature. The resulting precipi- 16) Perboni A., Sbampato G., WO9523149 (1995) [Chem. Abstr., 124,
tate was filtered and dried in vacuo to obtain 20 as colorless crystals (1.70 g,
67%), mp 218 °C (dec.). 1H-NMR (CD3OD) d: 3.65 (2H, t, Jꢁ7.5 Hz), 4.00
(2H, t, Jꢁ7.5 Hz), 4.43—4.56 (3H, m), 4.70 (2H, dd, Jꢁ8.4, 9.3 Hz). IR
(KBr) cmꢂ1: 3129, 3041, 1656, 1453, 1242, 1205, 1024. FAB-MS m/z:
254.9953 (Calcd for C6H11N2O3S3: 254.9932). MS m/z: 255 (MꢃꢃH).
b) To a solution of 17 (2.22 g, 8 mmol), MeOH (6 ml) and water (2 ml)
was added 10% Pd–C (0.22 g, dry reduced), and the mixture was stirred vig-
orously for 24 h under 500 kPa pressure of hydrogen at 40 °C. The catalyst
8503 (1995)].
17) Rossi T., Andreotti D., Tedesco G., Tarsi L., Ratti E., Feriani A., Pizzi
D. A., Gaviraghi G., Biondi S., Finizia G., WO9821210 (1998) [Chem.
Abstr., 129, 41033 (1995)].
18) Tanaka M., Kato K., Hakusui H., Murakami Y., Sato K., Ito Y.,
Kawamoto K., Antimicrob. Agents Chemother., 44, 578—582 (2000).
19) Sato M., Takemura M., Higashi K., Soga T., Matsumoto H., Nishi T.,
Eur. Patent EP0210883 (1987) [Chem. Abstr., 106, 213640 (1987)].
was removed by filtration, and to the filtrate was added Na2S2O3·5H2O 20) Nishi T., Sugita K., Otsuka M., Hayano T., Jpn. Patent JP08253483
(1.98 g, 8 mmol). After stirring for 22 h at 50 °C and being cooled to 5 °C, (1996) [Chem. Abstr., 126, 59806 (1996)].
Et3N (1.23 ml, 8.8 mmol) and chloroethylisothiocyanate (1.07 g, 8.8 mmol) 21) Otsuka M., Nishi T., Hayano T., Jpn. Patent JP09241260 (1997)
were added to the reaction mixture. The reaction mixture was stirred for [Chem. Abstr., 127, 293224 (1997)].
0.5 h and concentrated under reduced pressure to give crude 20. To a solu- 22) Otsuka M., Nishi T., Jpn. Patent JP09323994 (1997) [Chem. Abstr.,
tion of 28% NaOMe (1.53 g, 8 mmol) and MeOH (16 ml) was added crude 128, 114824 (1997)].
20 at room temperature with stirring, and the insoluble material was re- 23) Imura A., Ito M., Jpn. Patent JP10304893 (1998) [Chem. Abstr., 130,
moved by filtration. To the filtrate were added 1.33 mol/l HCl in MeOH
(7.4 ml, 9.6 mmol) and IPA (25 ml) at 5 °C, and the mixture was stirred for
15 min. The resulting precipitate was filtered and dried in vacuo to obtain 20
including 1 equivalent of NaCl as colorless crystals (gross 1.96 g, 85% pu-
rity, net 6.6 mmol, 82% yield).
24151 (1998)].
24) Akiba T., Saito T., Kanai K., WO9933830 (1999) [Chem. Abstr., 131,
102278 (1999)].
25) Akiba T., Saito T., Kanai K., Jpn. Patent JP11193284 (1999) [Chem.
Abstr., 131, 87913 (1999)].
Bis[1-(1,3-thiazolin-2-yl)azetidin-3-yl] Disulfide (21) The mixture of 26) Akiba T., Saito T., Kobayashi Y., Jpn. Patent JP11315066 (1999)
20 (gross 63.8 g, 51.8% purity, net 130 mmol) and conc. HCl (54.8 ml, [Chem. Abstr., 131, 336937 (1999)].
650 mmol) was stirred for 2 h at 55 °C. To the reaction mixture were added 27) Akiba T., Kobayashi Y. Saito T., Kanai K., Jpn. Patent JP11343281
MeOH (27.4 ml) and water (27.4 ml), and KHCO3 (104.1 g, 1.04 mol) was
then added to the mixture over 25 min at 5 °C. After stirring for 1 h, 30%
aqueous H2O2 (7.39 g, 65 mmol) was added to the mixture over 45 min, and
Na2SO3·7H2O (3.28 g, 13 mmol) and water (164 ml) were then added at
(1999) [Chem. Abstr., 132, 22825 (1999)].
28) Isoda T., Ushirogochi H., Satoh K., Takasaki T., Yamamura I., Sato C.,
Mihira A., Abe T., Tamai S., Yamamoto S., Kumagai T., Nagao Y., J.
Antibiot., 59, 241—247 (2006).
5 °C. The reaction mixture was stirred for 1 h at room temperature. The re- 29) Hikida M., Itahashi K., Igarashi A., Shiba T., Kitamura M., Anti-
sulting precipitate was filtered, washed successively with water and heptane
and dried in vacuo to obtain 21 as colorless crystals (20.9 g, 93%), mp 54—
55 °C. 1H-NMR (CDCl3) d: 3.36 (4H, t, Jꢁ7.6 Hz), 3.88 (2H, m), 3.92 (2H,
dd, Jꢁ5.3, 8.0 Hz), 3.94 (2H, dd, Jꢁ5.3, 8.0 Hz), 4.02 (4H, t, Jꢁ7.6 Hz),
microb. Agents Chemother., 43, 2010—2016 (1999).
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Abstr., 132, 49878 (1999)].
31) Chatterjee S. S., Triggle D. J., Chem. Commun., 1968, 93 (1968).
4.30 (4H, d, Jꢁ8.0 Hz). IR (KBr) cmꢂ1: 1613, 1344, 1116, 1005. EI-MS 32) Katritzky A. R., Cundy D. J., Chen J., J. Heterocyclic Chem., 31,
m/z: 347.0359 (Calcd for C12H19N4S4: 347.0493). MS m/z: 347 (MꢃꢃH).
3-Mercapto-1-(1,3-thiazolin-2-yl)azetidine Hydrochloride (1) To a
solution of 21 (17.3 g, 50 mmol) in MeCN (25 ml) were added Ph3P (16.2 g,
60 mmol), water (1.92 g, 100 mmol) and 8 mol/l HCl in MeOH (15.6 ml,
125 mmol), and the mixture was stirred for 1.5 h at room temperature. The
reaction mixture was triturated with THF (375 ml), and the resulting precipi-
tate was filtered and dried in vacuo to obtain 1 as colorless crystals (19.6 g,
93%). Physical and spectral properties are in accord with the disclosed
data.28)
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