JPS59144794A - Heterocyclic five-membered phosphorus derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is phenyl, phenoxy, lower alkoxy; R<2>-R<5> are H, lower alkyl, phenyl which may be substituted, lower alkoxycarbonyl, lower alkoxyalkyl, aryloxyalkyl; Y, Z are O, S; m, n are 1, 2 and m+n is 3). EXAMPLE:Phenylphosphonic N,N-bis(2-thioxo-1,3-oxazolydide). USE:A reagent for activating carboxyl groups in aminoacids on the peptide synthesis. PREPARATION:For example, the reaction of a compound of formula II (X is halogen) with another compound of formula III is carried out in the presence of a base such as sodium hydride in an inert solvent such as tetrahydrofuran, preferably at about 0 deg.C - room temperature for 45min to 25hr, to give the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 1,3-oxazolidine- or 1,3-
The present invention relates to thiazolinone-2-thione compounds, and more particularly to phosphorus derivatives of 1,3-oxazolidine- or 1.3-thiazolidine-2-thione compounds and methods for producing the same.

It has already been reported that 1,3-thiazolidine-2-thione has an excellent function as an activator for the carboxyl group of carboxylic acid. For example, Y, Nagao an
d E, FIJJITA, Hgterocycle
s.

17.537' (1982) 8. This document describes that carboxylic acid and 1,3-thiazolinone-2-thione are prepared in the presence of a basic catalyst such as pyridino and
3-Acyl-1,3-thiazolinone-2-thione obtained by dehydration with soimide (DCC) is easily converted to alcohol when treated with sodium borohydride, and converted to aldehyde when treated with diisobutylaluminum hydride. In addition, various amines,
It has been described that the desired amide can be derived selectively and in high yield by treatment with amino alcohol, aminothiol, etc., and therefore, 1゜5-3-thiazolinone-2-thione can be used to activate carboxylic acids. It has been revealed that the compound is extremely useful as a reagent.

However, 1.3-thiazolidine-2-thione requires a condensing agent such as DCC when activating the carboxylic acid, and there are some problems when this reagent is used industrially.

Therefore, the present inventors conducted extensive research in search of an activation reagent for carboxyl acid that does not require secondary reagents such as DCC as a carboxylic acid activation reagent, and as a result, found 1.
3-oxazolidine- or 1゜3-thiazolinone-2-
Is the phosphorus derivative of the on compound's proboscis a calzu? It has been found that this compound is extremely suitable as an activation reagent for phosphoric acid.

However, during our research, Ueno,
Yumino, Okawara, Proceedings of the 45th Spring Annual Meeting of the Chemical Society of Japan, 94.
4 (1982), 3-
The synthesis of acyl-1,3-thiazolinone-2-thione was reported. Therefore, the present inventor, N, N.
Further research was conducted on a new phosphorus derivative to replace -bis(2-thioxo-3-thiacylinonyl)phenylphosphorosoamide, leading to the creation of the present invention.

According to the present invention, in the general formula, 7(+ represents a phenyl group, phenoxy group or lower alkoxy group, and I R2, RX, R"JiUR" represents a hydrogen atom, a lower alkyl represents a substituted or unsubstituted phenyl group, lower alkoxycarbonyl group, lower alkoxyalkyl group, or aryloxyalkyl group; Y and Z each independently represent an oxygen or sulfur atom; m and n each independently represent 1 or 2 and an everlasting tree] is 3; However, when R' represents a phenyl group, Y represents an oxygen atom, Z represents a sulfur atom, and m is 1, R
1, R8, R4 and Ba do not represent hydrogen atoms at the same time.

As used herein, the term "lower" means that the number of carbon atoms in the group or compound to which the candy is attached is 611 M or less, preferably 4 or less.

In the above formula, the "lower alkyl group" may be linear or branched, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5eC-buty/l /, tert-butyl, n-
Examples include isoamyl and n-hexyl groups, and the "lower alkoxy group" is a lower alkyl-oxy group in which the lower alkyl moiety has the above meaning, and ? If you do,
Methoxy, ethoxy, n-propoxy, impropoxy, n-butoxy, tert-butoxy groups,
Examples of substituents on the benzene nucleus in the "substituted or unsubstituted phenyl group" include halodane atoms such as fluorine, chlorine, and bromine; lower alkyl groups such as methyl and ethyl; lower alkoxy groups such as methoxy and ethoxy; lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl; nitro groups and cyan groups, and the phenyl group may be substituted with 1 to 3 of these substituents.

The lower alkyl moiety in the "lower alkoxycarbonyl group" has the above meaning f:*L, and specific examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-f lopoquine carbonyl, and isonorodi. Examples of the "lower alkoxyalkyl group" include methoxymethyl, ethoxymethyl, methoxyethyl, and ethquinethyl groups; furthermore, the "aryloxyalkyl group" includes a, phenoxymethyl, phenoxy Examples include ethyl and naphthyloxymethyl groups.

Representative examples of the compound of (1) above are as follows.

Phenylthiophosphonic-N,N-bis(2-thioxo-1,3-thiazolid), Phenylthiophosphonic-N,N-bis(2-lO-thioxo-1,3-oxazolid), Phenylphosphonic- N,N-bis(2-thioxo-1,3-oxasilicito), phenylphosphonic-N,N-bis(2-4oxo-
4-ethyl-1,3-oxasilicito), phenylphosphonic-N,N-bis(2-thioxo-5-methyl-
1,3-oxazolid), phenylphosphonic-N
, N-bis(2-thioxo-4-isopropyl-1,3
-oxasilicito), phenylphosphonic-N,N-bis(2-thioxo-
5-phenyl-1,3-oxazolid), phenylphosphoric-N,N-bis(2-thioxo-1,3-thiasilicito), phenylphosphoric-N,N-bis(2-thioxo-
1,3-oxazolid), phenylphosphoric-N,N-bis(2-thioxo-
4-ethyl-1,3-oxtuzolidide), phenylphosphoric-N,N-bis(2-thioxo-4-methyl-
5-phenyl-1,3-oxasilicito), phenylphosphoric ~N,N-bis(2-thioxo-
5-methyl-1,3-oxazolid), phenylphosphoric-N,N-bis(2-f-oxo-5-phenyl-1,3-oxasilisito), phenylphosphoric ~N,N-bisC2-- y-oxo-4-methyl~5~
(2,5--jmethylphenyl)-1,3-oxazolid], sophenylphosphoric-N-(2-thioxo~1.3
-thiazolid), sophenylphosphoric-N-(2-thioxo-1,3
-oxazolid), duphenylphosphoric, #-(2-thioxo-4-
methoxycarbonyl-1,3-thiasilicito), sophenylphosphoric #-(2-thioxo-4-ethoxycarbonyl-1,3-oxazolisotone), sophenylphosphoric #-(2-thioxo-4-methyl-1 ,3-oxazolid), sophenylphosphoric-N-(2-thioxo-4,4-tumethyl-1,3
-oxazolid), sophenylphosphoric N-(
2-thioxo-4-ethyl-1,3-oxasilicito)
, sophenylphosphoric #-(2-thioxo-4-
Sophenylphosphoric N-(2-thioxo-4- Methyl-5-(2,
5-methylphenyl)-1,3-oxasilicito], = 13-sophenylphosphoric N-Cz-thioxo-4-(
4-Methoxyphenyl)-s-(4-methoxyphenyl)-1,3-oxasilisito], Soethylphosphoric N-(2-thiogyso1゜3-thiasilicito), Soethylphosphoric N-(2- Thioxo-1゜3-
Noethylphosphoric N-(2-thioxo-4-ethyl-1,3-oxazolid), Noethylphosphoric N-(2-thioxo-4-methoxycarbonyl-1,
3-oxasilicito), etc.

According to the invention, the compound of formula (1) has the general formula % formula %
() In the formula, X represents a halogen atom: 14-R' , can be produced by reacting the compound with the following in the presence of a base.

The reaction between the compound of formula (II) and the compound of formula (III) is generally carried out using an inert organic solvent, such as ethers such as soethyl ether, dimethoxyethane, tetrahydrofuran, sooxane, diglyme; trimethylformamide, trimethylacetamide. , amides such as hexamethylphosphoramide; hydrocarbons such as benzene, toluene, xylene, and cyclohexane; halocyanide hydrocarbons such as nochloromethane and carbon tetrachloride; trimethyl sulfoxide, etc. The reaction temperature is not strictly limited and can be varied widely depending on the type of starting materials, etc., but is generally about -20C to about 40'C, preferably (
Temperatures within the range of about OC to room temperature can be used.

The amount of the compound of formula (III) to be used for the compound of formula (If) varies depending on the number of m and n in the compound of formula (II).
2 to 6 of the compound of formula (III) per mol of the compound of
It is preferable to use the compound in a molar ratio, especially 2 to 4 molar, and when m-2 and n=1, the compound of 2 (I[l) is used per 1 mole of the compound of formula (II). 08-5 mol,
It is particularly advantageous to use it in a proportion of 0.8 to 2 mol.

The above reaction can be carried out in the presence of a base, and examples of bases that can be used include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as potassium carbonate and sodium carbonate; n-butyllithium, etc. metal alkoxides such as potassium-t-butoxide; amines such as diisopropylethylamine and triethylamine; these are generally 1 to 10 mol, preferably 1 to 10 mol per mol of the compound (I). 6
It can be used in molar proportions.

Under the conditions described above, the reaction can usually be completed in about 10 minutes to 50 hours, more generally about 45 minutes to 25 hours.

The obtained compound 2) can be separated from the reaction mixture and purified by methods known per se, such as recrystallization, chromatography, extraction, and distillation.

II (II) used as starting material in the above method
The phosphorus compound of formula (1) is a known compound, and has the odor-1 of formula (1).
7= X is preferably a chlorine atom.

In addition, at least some of the compounds of formula (■) are known, and even if they are new, they are similar to known compounds.
For example, it can be synthesized according to the following reaction formula) in which R2, R51R4, R5 and Z have the above meanings [for details, see
Y, Nagao, at alHTstrahed
ron Letters, 23, 201 (1982)
and Chtrmical Abstract, 53
, 2529 F (1959)].

The compound of formula (1) provided by the present invention has a
- Le→? As an activator for the carboxyl group of carbonic acid,
l? It can be advantageously used in various chemical reactions involving phosphoric acids. Hereinafter, the chemical reaction using the compound of formula (1) of the present invention will be explained in more detail.

(1) Synthesis of azetisonone derivatives by intramolecular amidation (cyclization) of various β=nia aminos: (A) In the formula, R10, R11, R'', Rls and R14 are each independently a hydrogen atom or a hydrogen atom directly open to reaction. Any shun chiroki who does not force,
For example, alkyloalkyl, aryl, aralkyl, alkenyl, arginyl, heterocycle, acy/1/amino or protected amino, protected carboxyl, alkoxy, arylekylthio, optionally protected hydroxyl, protected Represents a group such as a mercapto group, carbamoyl, or carbamoyloxy.

Intramolecular amidation of the β-amino acid of formula (A-) above is usually carried out using a suitable inert solvent, such as tetrahydrofuran, methyl chloride,
ionized hydrocarbons; acetonitrile, trimethylformamide, pyridine, ethyl acetate, etc., or at least one of these
This can be carried out by contacting the β-amino acid of formula (A) with the compound of formula 11 in a mixed solvent of seeds and water in the presence of a suitable sulfate base. The temperature of this intramolecular amidation reaction can vary widely depending on the type of β-amino acid of formula (A) and the compound of formula (11), but is generally a temperature between approximately room temperature and the reflux temperature of the reaction mixture. can be used.

The compound of formula (11) is conveniently used in a proportion of generally 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the β-amino acid of formula (A). It can be used generally in a ratio of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of β-amino acid. Examples of bases that can be suitably used here include, for example, sodium carbonate, potassium carbonate, triethylamine, Diisozolobyl ethylamine, birinone, somethylamine pyrisone,
-21=Gynoline, 2,6-lutidine, etc.

The intramolecular amidation can be completed under the above conditions, usually in 10 minutes to 50 hours, more generally in 05 to 30 hours.

(2) Synthesis of active amide from carboxylic acid and synthesis of various carboxylic acid derivatives via the active amide: @
R111-COOH+compound of formula (1)-ra (C) where R'' is a carboxylic acid residue, such as a linear, branched or alkyl alkyl, alkenyl or alkynyl group;
represents an aryl group, an aralkyl group, a heterocyclic group, etc., and these groups further include an atom or atomic weight that does not participate in the reaction,
For example, it may be substituted with a halodane atom, a cyano group, a nitro group, a retained hydroxyl group, a retained mercapto group, an alkoxycarbonyl group, etc.: R2, Ra, , R4, R5 and Zfdfn[self] have meaning.

The reaction between the carboxylic acid of formula (C) and the compound of formula (1) is carried out under substantially the same conditions as described in the previous section (1) for the treatment of the β-amino acid of formula (A) with the compound of formula (1). The following procedure can be carried out, which gives the active amide of formula 1). As shown in the reaction formula below, this activated amide is
reduction, or Dalignard's reagent, amines, alcohols,
Various carvone fermentation conductors can be obtained by conducting reactions such as thiols.

23-24- Each reaction shown in the above reaction formula can be carried out by a method known per se, for example, Y.

Nagao, et al., J. Chern.
Soc, Chem, Com.

330 (1978) and Y. Nagao, et.
at.

Tetrahedron Letters, 21,
841 (1981,).

In addition, the compound of formula (1) can be used not only for the intramolecular amidation of β-amino acids, but also for the synthesis of cyclic monoamides by intramolecular amidation of other amino acids (see the reaction formula below), or the amide of dicarboxylic acids and soamines. It can also be advantageously used in the activation of the dicarboxylic acid in the synthesis of a cyclic diamide by reaction (see reaction formula (2) below).

-25 = ■ HOOC-R"-COOH + Compound cyclic diamide of formula (1) The synthesis reaction of these cyclic monoamides and cyclic diamides can be carried out by methods known per se, for example, as described by Y., Nagao, et al. Chemisto
ry Letters, 159 (1980).

Furthermore, the compound of formula (1) of the present invention can be used as a reagent for activating the carboxyl group of an amino acid in peptide synthesis.

Further, when any one of K, R2, R", R4 and UR' represents a self-defined group other than a hydrogen atom, the compound of formula (1) has one or two asymmetric carbon atoms. Such an optically active compound of formula (1) can be used in an asymmetric aldol condensation or an asymmetric Diels-Alder reaction using the optically active compound as a chiral tin plate. Prostaglandin, etc.
It is conceivable that it could be used for the synthesis of useful natural products such as indole alkaloids and calcomycin. An example of such asymmetric synthesis is shown in Reference Example 2 below.

The present invention will be explained in more detail with reference to Examples below.

Example 1: To a suspension of sodium hydride (0,72y) in tetrahydrofuran (20 ml), 2-thioxo-
1,3-oxazolidine (2f, 0.019 mol)
A tetrahydrofuran (20me) solution of was added dropwise. After stirring at room temperature for 1 hour, a solution of phenylphosphonic acid trichloride (2,1F, 0.011 mol) in tetrahydrofuran (20 mg) was added dropwise under water cooling, and the mixture was stirred at room temperature for 2 hours.

The reaction mixture was poured into water, and the precipitated crystals were dried from house to house.
, colorless crystals (2,621) were obtained: yield 84% Melting point: 188r (decomposed) (recrystallized from chloroform) NM'R (C and C1s*ppm): 4.20 (m,
4H), 4.68 (t, 4#), 7.65 (m,
31f), 8.26 (m, 2#) Elemental analysis value 2012H1,N203PS, C (%
) H (%) N (%) S (%) Calculated value 43
．． 89 &99 8.53 19.53 Actual value 43.47 3.96 &64 19.4°Synthesized from phenylthiophosphonic acid chloride and 2-thioxo-1,3-thiazolidine in the same manner as above: Yield 8o % M point: t34-137° (Chloro injection\lumuacetic acid 2
9- recrystallized from chill) NMR (CDCl!+ppm): 3.42 (t,
4H), 4.50 (tyt, 4ff), 7.53 (
m, 311), 8.60 (m, 2B) Elemental analysis value: C1□11,3N, PS, C (%)
B (%) N (%) SC%) Calculated value 3&28
3.48 7.44 42.57 Actual value 38
,01 3.41 7.32 42.50 Synthesized from phenylphosphonic acid dichloride and (-)2-thioxo-4-ethyl-1,3-oxazolidine in the same manner as above: Yield 70% 30- Yellow Oil (purified by column chromatography) [α]
So (C=i, O, CBCI, ): +255.
16NMR (CDCI, ppm): 0.76 (
m, 6H), t, s5 (m, 4B), 4.33 (m
, 3#), 4.76 (m, 3H), 7.60 (m
, 3M), s, 5s (m, 2#) Elemental analysis value: C8°H□N, O, PS, C (%)
H (%) N (%) S (%) Calculated value 49
．． 99 5.51 7.29 16.68 Actual value 50.05 5.46 7.15 16.59 Example 2: (-)2-thioxo-4-ethyl-1,3-oxazolidine (],, 1 f , 8.4 mmol) in tetrahydrofuran (30+ml), sodium hydride (0.222 f) was added portionwise under water cooling and stirring.

After stirring for another 15 minutes while cooling with water, phenylphosphoric acid chloride (
0,886F, 4.2 mmol) and cooled for 30 minutes under water cooling.
minutes and then stirred at room temperature for 3 hours. The reaction mixture was diluted with water (5
oy), and the precipitated crystals were dried individually to obtain colorless crystals: Yield 73% Melting point: 165-172c [ct"J', 3 (C=o, 6.ClICl5) Ni 170.7° NMR (CDCI3.ppm): 0.
56 (t, 3H), x, oo (t, aR), 1.3
0 (m, 2#), 2.00 (m, 2H), 4.20-5
．． 10 (m,.

6H), 7.43 (m, 5H) Elemental analysis value: C,,H,,H,O,PS,C
(%) H (%) N (%) S<%) Measurement: Value 47
．． 99 5.29 7.00 16.01 Actual value 48.03 5.20 6.88 15.88 Synthesized from phenylphosphoric acid dichloride and 2-thioquine-1°32-3-thiazolinone in the same manner as above.

Melting point: 175-178tZ' NMR (CDC1,, ppm): 3.45 (d t
, 4H), 5.65 (d t , 4B), 7.3
6 (helmet, 5H) Elemental analysis value: C+tH+5N20t
As PS4, C (%) HC%) N (%)
S (%) calculated value 38.29 3.4.8 7.4
4 34.06 Actual value 38.09 3.42 7.
38 34.12 Synthesized from phenylphosphoric acid dichloride and 2-thioxo-1°3-oxazolidine in the same manner as above.

33- Melting point: 195-197C NMR (CDCI3.ppm): 4.20-4.80
(m.

8 II), 7.33 (m, 511) Elemental analysis value: C82HI! As N204PSt, C (%)
Ii (%) N (%) S (%) Calculated value 41.
86 3,81 8.14 18.62 Actual value
41.92 3.85 8.20 18.54 Synthesized from phenylphosphoric acid chloride and (+)2-thioxo-4-methyl-5-phenyl-1,3-oxazolidine in the same manner as above.

Melting point: 203~208C [α Cat (C,, -1, Ot, CHCl,) Ni 1
34.18HMR(CI)C1,,ppm): 0
．． 50 (d, 311), 1.20 (d, 3
l-1), 5. ], O(d q .

2B), 6.13 (dd, 211), 7.45 (
m, 15H) Elemental analysis value: C,,If,,NtO4PSt,
C (%) H (%) N (%) S (%) Calculated value
59.53 4.80 5.34 12.22 Actual value 59.46 4.63 5.28 12.17
Example 3: Rigid (-)2-thioxo-4-methoxycarbonyl-1,3
- Sodium hydride (0.24 f ) was added little by little to a solution of thiazolinone (1,97, 0.01 mol) and hisophenyl phosphoryl chloride (2,97 F) in tetrahydrofuran (35 m/) under water cooling and stirring. . 1 at θ~5C
After stirring for 30 minutes at room temperature, the reaction solution was diluted with water (1
50+++/) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica dal chromatography (eluent: chloroform) to obtain a yellow oil (3,6r).
Obtained: Yield 88% [α]so(C=1.0, CHCl3) Ni 11
3.2°NMR (CDC1,, ppm): 3.45 (
s, 3H), 3.52 (m, 2#), 5. s 6
(m, IH), 7.33 (m, 10H) Elemental analysis value: C, 7H, 6No, PS2 as 36-C (%) H (%) N (%) S<%) Calculated value 49.87 3 ,94 3.42 15.66
Actual value 49,56 3.96 3.22 15
．． It was synthesized from 702-thioxo-1,3-thiazolisine and diphenylphosphoric acid chloride in the same manner as above.

Melting point: 107-109t:' NMR (CDCI, PP): a, ao (t, 2#)
, 4.40 (t, 2H), 7.36 (s, 1oH
) Elemental analysis values: C, IIB, 4No, PS,
C (%) 11 (%) N (%) S (%) Calculated value 51.28 4.02 3.99 18.25
Actual value 51.09 4.08 4.05 18.
20 Sophenylphosphoric N-(2-thioxo-2
-Synthesized from -thioxo-1,3-oxazolidine and sophenylphosphoryl chloride in the same manner as above: Yield 72% Melting point = 112-114tr NMR (CDCl, ppm): 4.03 (t
, 2H), 4.47 (t, 2H), 7.33
(m, 1077) Elemental analysis value: C,,,H14N
O, PS as C (%) H (%) N (%) S (
%) Calculated value 53.73 4.21 4.18
9.56 Actual value 53,60 4,15 4.16 9
．． 55(-)2-thioxo-4-ethyl-1,3-oxazolidune and sophenylphosphoric acid loridotocara were combined in the same manner as above: Yield 80% Melting point: 135-137
T? [αTaku (C=1.0, CBCl, ): +71.2
8HMR (CDCl, ppm): 0.73 (t
, 3H), 1.56 (m, 211), 4.28
(m, 3#), 7.3F+ (慴, toH) Elemental analysis value: C (%) as C, 7H, 8No4PS
H (%) N (%) S (%) Needle calculation 56.1.
9 4.89 3.85 8.82 Actual value 56
,25 5,03 4.01 8.75 2-thioxo-4,4-dimethyl-1,3-oxazolidine and sophenyl phosphoric acid loridotocara Synthesized in the same manner as above: Yield 70% Melting point = 98-1010 0CN (CDCI8 .ppm): 1.32 (s
, 6H), 4.13 (8,2H), 7.36 (
m, 10H) Elemental analysis values: C, Ji, 8No, PS as C (%) H (%) N (%) S (%) Calculated values 56,19 4,99 3.85 8.8
2nd demonstration 1st shift 56,09 5.12 3,
90 8.8840- (+)2-thioxo-4-methyl-5-phenyl-1,
Synthesized from 3-oxazolidine and sophenyl phosphoryl chloride in the same manner as in Section 1: Yield 76% Yellow oil [α]', , (C=LO, CHCl,): +9.9° NMR (CDCI, , ppm): 0.65 (d
, 3H), 4.56 (Full, IH),
6. a o (d, ], H), 7
, 30 (tn, l 5 II) elemental analysis value:
C2! C (%) H (%) as H, oNO, PS
N (%) S (%) Calculated value 62,11 4.74
3,29 7.54 Actual value 62.03 4.68
139 7.60 Example 4: 41-Noethylphosphoric #-(2-thioquine-1゜2-
Thioxo-1,3-oxazolidine (1,Or, 9.7
To a solution of (mmol) in tetrahydrofuran (301 nl) was added hydrogenated IJium (0.4:M) little by little while stirring under water cooling, followed by stirring under water cooling for 15 minutes. Diethyl phosphoric acid chloride (1,68f.

9.7 mmol) and cooled with water for 30 minutes, then at room temperature for 30 minutes.
Stir for hours. The reaction solution was poured into water (80 yd) and extracted with chloroform. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a colorless oil (2,1F): yield 91% NMR (CDCl, ppm): 1.40 (t,
6M), 4.1s (dt, 2H), 4.27 (q, 4B
), 4.6 6 (d t , 2B) as elemental analysis value: C, H14No4Pg as C (%)
H (%) N (%) S (%) Calculated value 35,14
5,90 5.85 13.40 Actual value 35.
02 5.79 5.62 13.18 Synthesized from 2-thioxo-1,3-thiazolinone and diethyl phosphoric acid chloride in the same manner as above.

Yellow oil NMR (CDCl, ppm): 1.39 (t
, 6B), 3.45(t, 211n, 4
．． 2 3 (q, 411 n, 4.40
Ct, 2H) Elemental analysis value: C (%) as C, H, 4No, PS,
HC%) N (%) S (%) Calculated value 32L9
3 5.53 5.49 25.12 Actual value 3
2.85 5,48 5.36 25.08 Reference Example 1: Synthesis of β-lactam 1-1. N-pentulu-2-azenanonone 3-pentulaminopropionic acid (18pr9.01 mmol) and phenylphosphonic-N.

N-bis(2-thioxo-1,3-oxazolid) (
66 ~, 0.2 mmol) of acetonitrile (2 (1 m
/) Diisopropylethylamine (0,09-) in solution
was added and refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the residue was
Purified by silica column chromatography (eluent: ethyl acetate) containing % silver nitrate to give a colorless oil (12,6
Tn9) was obtained: yield 78% NMR (CDCIB, ppm): 2.95 (2H
,t.

44- J=4), 3.15 (2, H, t, J=4), t 38
(2H,s) ,7.31 (511,tn,
)Mass mle 161 (Af+)IR7,
A 1730 Elemental analysis: C, oH,, HN as No Calculated value (%) 74.51'6.88 8.69
Actual value (%) 74.20 7.09 8.4
3#-(2,4-nomethoxy)pentulyaminopropionic acid (239V, 1 mmol) and diphenylphosphoric-7V-(2-thioquine-4-methoxycarnilu-1,3-thiasilicyto (4077V, 2 mmol) ) Diisopropylethylamine (0.9 ml) was added to a solution of noacetonitrile (200 m/), and the mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the residue 45% was purified by column chromatography on a silica column containing 3% nitric acid and 3% silver. Purified by E (bath solution: ethyl acetate) to produce a colorless oil (
200m9) was obtained: yield 91% NMR (CI) C18
, ppm)', 2.93 (2H, m), 3, 20
(2H, m), 3.82 (6H, s), 4.3
5' (2, H, 8), 6.50 (211, m), 7.
20 (111, d, J=9) Elemental analysis value: C1□H,, No, CHN Calculated value (%) 65.14 6,83 6.3
3 Actual measurement value (%) 64.96 6.58 6.
302C1)-2-(2-tritylaminothiazole-
4-yl)-2-methoxyiminoacetamide]-3-benzolaminozolobionic acid (62nr9+o, 1 im') mol) and phenylphosphonic-N.

N-bis(2-thioxo-1,3-oxasilicito) (
65,7■, 0.2 mmol) of acetonitrile (20
ml) solution, soyisopropylethylamine (0.09
ml was added and the mixture was refluxed for 4 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica column chromatography (eluent: methylene chloride/ethyl acetate/benzene-1/1/
1) to obtain the title compound (38.7 da): yield 65% NMR (CDCIS, ppm): 3.82 (5H,
m), 4.40 (311, m), 6.5o (x#, s
), 7, 35 (20H, m) Elemental analysis value: Cs, iHml N503 S as H
NS Calculated value (%) 69,86 5.19 11.64
5.33 Actual value (%) 69.93 5.11 11
．． 49 5.40 Reference Example 2: Asymmetric aldol-fused propionic acid (7,4f, 0.1 mol) and (+)
Phenylphosphonic-N,N-bis(2-thioxo-
4-ethyl-1,3-oxasilicito) (28,55'
, 0.07 mol) of dimethylformamide (150
yd) Triethylamine (x5r) was added to the solution, and after stirring at room temperature for 24 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica dull column chromatography (bath solution: benzene) to obtain a pale yellow oil (13,2?): Yield 70% [α]23 (C=1.o, C
):/Cj,): + 108.1.

NMR (CDCl, ppm): 1.06 (m
, 6H), 1.83 (m, 2H), 3.23 (m
, 2#), 4.30 (m, 311) 24(-) 3-hydroxy-3-phenyl-48- methyl 2-methylpropionate (+) 3-propionyl-4-ethyl-1,3-oxazolidine- 2-thione (0,381'.

Z05 mmol) in sochloromethane (4 ml) solution,
Under OCK cooling and stirring, trifluoromethanesulfonic acid 9-borabicyclo[a, a, xl nonane (o, 6r),
Subsequently, noisopropylethylamine (0,3159,
2.44 mmol) was added thereto and stirred for 30 minutes under OC. Next, the reaction solution was cooled to 78 U, and benzaldehyde (0
, 24, 2.26 mmol) was added, and at the same temperature, 30
The mixture was further stirred at room temperature for 1.5 hours. The reaction solution was adjusted to pH7,
0 phosphate buffer (4,8-), methanol (11,1-)
The mixture was added to a mixture of 30% hydrogen peroxide (4.8 Tn!) and stirred for 1 hour. After methanol was distilled off under reduced pressure, the mixture was extracted with ether, the extract was dried over anhydrous sodium sulfate, and then the ether was distilled off. The residue was dissolved in methanol (9 ml), and a 28% methanol solution (0.3 mL) of sodium methoxide was added to the mixture under OC, and the mixture was stirred for 5 minutes. The reaction solution was poured into @Japanese brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel filtrate (bath solution; n-hexane/ether-7/3) to obtain a colorless oil (329m9): yield 83% [α]so(co, + 2 , CBCI, ) knee 2
0.5°NMR (CDCI3.ppm): 1.12
(d, 3#, J=7), 2.77(m, 1#
), 3.70 (8°3H), 5.13 (d, IH, J
=4), 7.41 (8,5H) Elemental analysis value: C41HI40. As CH Calculated value (%) 68.02 7.26 Measured value (%)
) 67.93 7.35 Reference Example 3: Synthesis of N-butylbenzamide Phenylphosphonic-N,N-
Bis(2-thioxo-1,3-oxazolidine) (1
,64f,.

Benzoic acid (6,1, 5 mmol) and diisopropylethylamine (2,7 ml) were added to a solution of 5 mmol) in acetonitrile (s 0 ml) and refluxed for 1 hour.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform) to obtain colorless crystals (0.88P).

Melting point: 140-141C NMR (CDCI, , ppm): 4.33 (
t, 2H), 4.67 (t, 2B), 7.2
5-7.73 (m, 5#) MS", mAe 207 (M) Elemental analysis value 20 IoH, N01S, C (%) H (%
N (%) Total value 57.95 4,38
6.76 Actual value 57.79 4,57 6
．． 653-2 N-Butylbenzamide 3-benzoyl-1,3-oxazolidine-2-thione ('2.Q 7 r , 0.01 mol) in dichloromethane (15 mol) was dissolved in n-butylamine at room temperature with stirring. ((1,8f, O, (111 mol) of dichloromethane<5yd) g solution was added and stirring was continued until the initial yellow color disappeared (about 5 minutes).The solvent was distilled off under reduced pressure and the residue was transferred to the power receiving station. The amide (1,761) was obtained as a colorless oil by silica column chromatography dissolved in chloroform and containing IO% silver nitrate at 1 WfM, N-butyl pen: 99% yield NM'R (CDCI, , ppm):
0.91 (3#, t.

J = 6 Hz, -C1i, ), 1.1~1
．． 8 (4#.

m, -〇M, -X 2), 3.37 (211,
q.

52- J = 6 II z , -CONHCμ, C1i, -
), 7.0 to 7.9 (6H, m, C, H, jNH)
Reference Example 4 Synthesis of benzaldehyde 3-benzoyl-1,3-oxazolinone-2-thione (9.1 mmol of 2071n)
A)/dichloromethane (dissolved in 25 ml of anhydrous mixed solvent, maintained at -50p under a nitrogen stream, and while stirring, a 20% n-hexane solution (1.5 me) of diisobutylaluminum hydride was added dropwise, until the initial yellow color The reaction mixture was stirred until it disappeared (about 5 minutes). A small amount of methanol was added to the reaction mixture, and the mixture was carbonated. After washing with an IJ solution and water, the mixture was dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain colorless oily benzaldehyde (959): Yield 90% 53-

Claims (1)

[Claims] 1. In the general formula, RI represents a phenyl group, phenoxy group or lower alkoxy group; R2, R51R6 and RI each independently represent a hydrogen atom,
Represents a lower alkyl group, a substituted or unsubstituted phenyl group, a lower alkoxycarbonyl group, an alkoxyalkyl group or an alkoxyalkyl group; Y and Z each independently represent an oxygen or sulfur atom; m and η , are each independently 1 or 2, and m +
The sum of n is 3; however, when R1 represents a phenyl group, Y represents an oxygen atom, Z represents a sulfur atom, and m is 1, R
11X R'', R and R1 shall not represent hydrogen atoms at the same time. 2. General formula % Formula % () In the formula, R1 represents a phenyl group, a phenoxy group or a lower alkoxy group. Representation; X represents a halodane atom; Y represents an oxygen or sulfur atom; m and n are each independently 1 or 2, and the sum of m+n is 3; , R4 and R each independently represent a hydrogen atom,
represents a lower alkyl group, a substituted or unsubstituted phenyl group, a lower alkoxycarbonyl group, a lower alkoxyalkyl group, or an aryloxyalkyl group; Z represents an oxygen or sulfur atom; In the characteristic general formula, R1, R2, R3, R4, RI XY. ZX? 7+, and n have the meanings given above, provided that R
When 1 represents a phenyl group, Y represents an oxygen atom, Z represents a sulfur atom, and m is 1, R2, R3,
A method for producing a compound represented by: R4 and R5 do not represent hydrogen atoms at the same time.