JPH0565291A - (3s,4r)-3-(1(r)-(t-butyldimethylsilyloxy)ethyl)-4- (1-oxo-3-thiolanylthio)thiocarbonyl)azetidin-2-ones and improved process for producing their intermediates - Google Patents

Abstract

PURPOSE: To provide a new compd. which acts as an intermediate for the production of a synthetic intermediate of an antibacterial penem compd. and realizes a high yield of the synthetic intermediate of the antibacterial penem compd.

CONSTITUTION: This compd. is expressed by formula I. The compd. is obtd. by allowing a corresponding chloro deriv. to react with excess formic acid in the presence of an org. base (preferably triethylamine, pyridine) at 0 to 10°C. After the compd. expressed by formula I is allowed to react with a compd. expressed by formula II, the product is collected by nonaqueous treatment so as to obtain the objective compd. expressed by formula III which is a synthetic intermediate of antibacterial 5R,6S-6-[1(R)-hydroxyethyl]-2-(1-oxo-3- thiolanylthio)-2-penem-3-carboxylic acid.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

This invention relates to formulas in which the 4-position substituent of formula (I) includes racemic, cis- and optically active forms:

[Chemical formula 12] ( 3S , 4R ) -3- [1 ( R )-(t-butyldimethylsilyloxy) ethyl] -4- [1-oxo-3-
It relates to an improved process for preparing thiolanylthio (thiocarbonyl) thio] azetidin-2-one. The present invention also relates to improved processes for the preparation of specific intermediates for compounds of formula (I) and novel intermediates for compounds of formula (I).

[0002]

The compound of formula (I) has the formula (II):

[Chemical 13] [The above equation, racemic 1-oxo-3-thiol Ani Lucio portion of Formula (II), sill - and optically representing the active form] 5 R anti bacterial, 6 S-6-[1 ( R ) -Hydroxyethyl] -2- (1-oxo-3-thiolanylthio) -2-penem-3-carboxylic acid, pharmaceutically acceptable salts and esters thereof, especially pivaloyloxymethyl ester Is a useful intermediate.

For the synthesis of penem compounds of formula (II), see US Pat. Nos. 4,595,539 and 4,6.
19, 783. The first patents included xanthates or trithiocarbonates such as p-nitrobenzyl-2- (4-alkylthio-2-oxo-).
1-azetidinyl) -2- [2-R ₁ thio (thiocarbonyl) thio] acetate, wherein R ₁ represents an organic moiety, and desulfurization, and an electrophilic reactant such as acetyl chloride is added. And the corresponding p-nitrobenzyl-2-
(4-alkylthio-2-oxo-1-azetidinyl)
3-acetylthio-3 to obtain a _{(2-R 1-thio)} acrylates are described. The acrylate derivative is then converted to the corresponding 4-halo derivative by halogenation and cyclized to give the penem.

A second US Pat. No. 4,619,783 describes xanthates or trithiocarbonates such as p-nitrobenzyl 2- {4-alkylthio-3-.
[1-p-Nitrobenzyloxycarbonyloxy) ethyl] -2-oxo-1-azetidinyl} -2- (R ₁
Consisting of desulfurizing an oxythiocarbonylthio) acetate to the corresponding 2- (R ₁ oxythiocarbonyl) acetate, followed by halogenation to the corresponding 4-halo derivative and cyclization to give the 2-penem. The method is described.

Each of the above patents also includes 4-acetoxy-
3-R-azetidin-2-one (R = H, 1-hydroxyalkyl or protected 1-hydroxyalkyl)
By reacting with the appropriate sodium salt of an alkanethiol to give the corresponding 4-alkylthio-3-R-
Switching to azeticin-2-one is described.

In US Pat. No. 4,619,924, 4
-Acetoxy-3 [1 (R)-(t-butyldimethylsilyloxy) ethyl] acetidin-2-one was prepared according to the formula N
_{^{a + R 1 -S-C (}} S) -S - ( wherein, _{R 1} is an organic moiety) is reacted with sodium or potassium trithiocarbonate of the corresponding 4-R- thio (thiocarbonyl) Thioazetidin-2-one [eg, formula (I)
] Of the azetidin-2-one
The conversion to compounds of I) is described.

Compounds of the formulas (I) and (II) and their (3 R , 4 R ) -4-acetoxy-3- [1 ( R ))
For the preparation from-(t-butyldimethylsilyloxy) ethyl] azetidin-2-one, see US Pat.
No. 739,047.

Formula (III):

[Chemical 14] A large number of (3 S , 4 R ) -3- [1] (wherein there may be a protecting group on the hydroxy group and / or the nitrogen atom)
The preparation of ( R ) -hydroxyethyl] -4- (X-substituted) azetidin-2-ones and their use as intermediates have been reported in the literature. Representative examples of such compounds are shown below:

(3 R , 4 R ) -3- [1 ( R )-(t-
Butyldimethylsiloxy) ethyl] -4-methylsulfonylazetidin-2-one (Formula III, X = SO ₂ CH
₃ ) of (3 S , 5 R , 6 S ) -6-bromo-6- [1.
For a multi-step synthesis from methyl ( R ) -hydroxyethyl] penicillinate, see Tetrahedro et al.
n Lett . 23, 4021 (1982). This synthetic method involves protecting the hydroxy group of the 6-substituent by debrominating the starting material with tin hydride followed by silylation with t-butyldimethylsilyl chloride and oxidizing the resulting product. A cis-sulfone derivative is obtained. The key step of this synthetic method, reported to be the isomerization of cis-sulfone to trans-sulfone, was carried out at room temperature in catalytic amounts of 1,5-
Diazabicyclo [4.3.0] non-5-ene (DB
N) can be done "satisfactorily". Ring-opening of trans-sulfone by treatment with excess methyl iodide and potassium t-butoxide gives 3- [1
( R )-) t-Butyldimethylsiloxy) -ethyl]-
4-Methylsulfonylazetidin-2-one is obtained.

However, as reported by Hirai et al. (Supra), DBN isomerizes cis-sulfone to trans-sulfone, but cannot completely isomerize a protected hydroxyethyl group. People have found it. Excess methyl sulfone and potassium iodide t-
Subsequent ring-opening of the trans-sulfone to give the corresponding azetidinone was followed by the method of Hirai et al. By treatment with butoxide to give a mixture of isomers.

Japanese Unexamined Patent Publication (Kokai) No. 58-109490, issued on June 29, 1983, has the formula (IV):

[Chemical 15] Of the 5,6-cis compound to the corresponding trans compound converts the cis compound to DBN, DBU (1,8-diazabicyclo [5.4.0] -undec-7-ene), triethylamine and N, N-. It is stated that this can be done by treatment with any of various organic bases such as dimethylaniline. It is stated here that the amount of the base used may be a catalytic amount, but is usually 0.1-2 equivalent. However, there are only examples in which only DBN was used as the isomerizing agent.

X in Yanagisawa et al. (Supra) is SO ₂ C ₆ H
_The method for synthesizing the compound of formula (III) which is ₅ , is to convert epoxysulfone (V) to azetidin-2-one (III-A) in 82% yield in one step,

[Chemical 16] This is done by reaction with n-butyllithium (2 equivalents) in hexamethylphosphoric triamide (HMPT) at -50 ° C in an inert atmosphere. If the reaction is carried out in the absence of HMPT, the temperature has to be raised to room temperature. The product is a 3: 1 mixture of compound (III-A) and its diastereomer.

In US Pat. No. 4,614,614, compound (V) is treated by treating compound (V) with a source of fluoride ions such as tetra (n-butyl) ammonium fluoride in a neutral solvent. ) Is converted to compound (III-A). In the general description, the 3-substituent is 1-hydroxyethyl or hydroxymethyl, optionally protected, and the 4-substituent is especially -S.
O ₂ R ₃ (R ₃ is an organic group bound to the S atom by a carbon atom not bound to hydrogen) or the 4-substituent is COOR ₃ ′ (R ₃ ′ is bound to hydrogen). (3S) 3,4-trans disubstituted azetidin-2-one, which is an organic group bound to the O atom of the carboxy group by a carbon atom which is not. Representative examples of R ₃ and R _{3 ',} t-lower alkyl, aryl or a substituent such as phenyl methoxy, substituted aryl, such as methyl or nitro.

In Shibasaki et al. (Supra), X is SO ₂ C ₆ H
_5, Compound (III) is, X is reported to be produced by oxidizing the corresponding compound is SC ₆ H _5. The relevant oxidation procedure is described by Yoshida et al. (Supra).

Shiozaki et al. (Supra) are compounds (III,
X = SO ₂ C ₆ H ₅ ) is a compound (III, X = OCO
By treating CH ₃₎ with two equivalents phenyl sodium sulfonate, 63% yield, are reported to be produced.

The preparation of compound (III, X = Cl) is disclosed by Arpegianie et al. (Supra).
This method is carried out using a suitable disulfide [compound (III, X
= -S-S-2-benzothiazolyl) and 1 molar equivalent of chlorine. It is described as unstable to silica gel chromatography. Endo (above) is a compound (III, X = t-butyl sulfide)
It is taught to make this by chlorinolysis of 2 with 2 equivalents of chlorine. He notes that this compound is “rather stable at room temperature, but rather stable at −20 ° C.” and this is due to the acetoxy derivative [compound (III, X═OCOCH ₃ )]
It exhibits high reactivity at low temperature compared to.

European Patent No. 181831 describes X
Is a general description of compounds of formula III in which is OCOR ₃ (R ₃ is lower alkyl, phenyl or substituted phenyl). For example, the latter group is mono- or tri-substituted by groups such as lower alkoxy, lower alkyl and / or halogen.

US Pat. No. 4,585,767 describes 4
The substituent is a group displaceable by a nucleophilic group and this is especially acyloxy (eg acetoxy),
6- (1 from 3- (1-hydroxyethyl) -4-substituted-azetidin-2-one that is sulfonyl (eg, phenylsulfonyl) or halo (eg, chloro).
-Hydroxyethyl) -2-aryloxypenem is described.

A compound related to the compound of formula (III),
Provided that the 3-position is unsubstituted or substituted with 1 or 2 methyl groups, and the 4-substituent is -YZ.
(Compounds wherein Y is O, S or OS ₂ and Z is alkyl, phenyl, substituted phenyl, alkanoyl, benzoyl or substituted benzoyl are represented by Claus
s), Liebigs Ann. Chem. 539
(1974). The 4-acyloxy derivatives listed above act as reactants for other 4-substituted derivatives by nucleophilic substitution of the acyloxy group.

(3 S , 4 R ) -3- [1 ( R )-(t-
For the preparation of butyldimethylsilyloxy) ethyl] -4- [1-oxo-3-thiolanylthio (thiocarbonyl) thio] azetidin-2-one (I) and their recovery from the reaction mixture, 1988. April 1
There is described in U.S. Patent No. 4,739,047 of 9th issue, (3 R, 4 R) -4- acetoxy -3- [1 (R)
- (t-butyldimethylsilyloxy) ethyl] azetidin-2-one (I) and sodium 3S- [thio (thiocarbonyl) thio] thiolane 1 (R) - by reaction with oxides, (3 S, 4 R) -3- [1 ( R )-(t
-Butyldimethylsilyloxy) ethyl] -4 [1
The preparation of (R) -oxo-3S-thiolanylthio (thiocarbonyl) thio] azetidin-2-one is illustrated. The product is recovered by quenching the reaction mixture with saturated ammonium chloride solution, then extracting the product with ethyl acetate and concentrating the dried extract. The crude product is purified by slurrying it in isopropyl ether.

The above process involves an aqueous step, which is sufficient for small scale reactions, but for large scale, compound (I) is under aqueous recovery treatment. Not suitable because it lacks stability.

[0022]

DISCLOSURE OF THE INVENTION The present invention provides 5 R , 6 S
-6- [1 ( R ) -Hydroxyethyl] -2- (1-oxo-3-thiolanylthio) -2-penem-3-carboxylic acid and their pharmaceutically acceptable salts and pivaloyloxy It provides an improved method for producing methyl esters.

More specifically, the present invention relates to cis- and optically active (3 S , 4 R ) -3- [1 of formula (I).
( R )-(t-Butyldimethylsilyloxy) ethyl]
-4 [1-oxo-3-thiolanylthio (thiocarbonyl) thio] azetidin-2-one (I), and an improved process for the preparation of the specific (3 S , 4 R ) -3- [1.
( R )-(t-Butyldimethylsilyloxy) ethyl]
-4 (substituted) azetidin-2-one
The 4-substituent is SO ₂ Y (Y is methyl or 2,4-
If it is dinitrophenyl, route (1):

[Chemical 17] By or, if its 4-substituent is SO 2 C 6 H 5 , route (2):

[Chemical 18] Embedded image wherein Ar is an amino protecting group.

Furthermore, the present invention provides a novel intermediate (VI) for producing compound (I):

[Chemical 19] And to an improved non-aqueous method of recovering compound (I) from a reaction mixture.

[0025]

In the method of the above route (I) reported by Hirai et al. (Supra), DBN is used as a base for isomerizing compound (a) from cis to trans form. .. They report that at room temperature a catalytic amount of DBN in methylene chloride gives satisfactory conversions. However, DBN is unable to completely isomerize cis (a) to trans (a), which results in ring opening of the isomerization reaction product resulting in a mixture of cis and trans forms of compound (b). The applicants have found that the following can be obtained.

However, it has been found that DBU is completely isomerized from cis (a) to trans (a). Ring-opening of the isomerization product yields only the trans form of compound (b), at which point the isomers can be separated either after the reaction step using compound (b) as an intermediate. There is no need to do it.

The reaction with DBU is carried out in substantially the same manner as the reaction with DBN. The amount of DBU used based on reactant (a) can vary from catalytic amounts (less than 0.1 molar equivalent) to large excesses. In order to carry out complete isomerization of cis form to trans form,
More than 1 molar equivalent of DBU must be used.
In order to effect almost complete isomerization of cis form (a) to trans form (b), DB in the range of about 1.0-2.0 molar equivalents is used.
We have found that U is particularly useful. Methylene chloride works well as an inert solvent for the reaction. Substantially complete isomerization of the cis form to the trans form takes place with a reaction time of about 5-90 minutes at ambient temperature. After beta elimination of the thiazolidine ring, an alkylating or arylating agent, such as methyl iodide, 2,4-dinitrofluorobenzene or 2,4-dinitrochlorobenzene, is added to the isomerization reaction product to give a compound of formula (b ) Compound is produced. actually,
After the beta elimination of the thiazolidine ring, an alkylating or arylating step is carried out by adding an alkylating or arylating agent to the isomerization reaction product,
A 4-fold excess of the above drug is used. The reaction is a one-pot process. That is, it is carried out in a single reaction without isolation of the intermediate. The reaction temperature is about 0-10 ° C. when using methyl iodide as the alkylating agent,
When using an arylating agent, it is about 20-50 ° C. The product is recovered by known procedures.

Conversion of compounds of formula (b) to compounds of formula (c) is carried out by oxidation procedures reported in the literature.

The process of route (2) for converting glycidamide (d) to azetidinone (e) was carried out by using a glycidamide in a reaction-inert solvent such as tetrahydrofuran, Yanagisawa et al. (Supra). It is carried out by treatment with lithium t-butoxide, which is a weaker base. The use of lithium t-butoxide has advantages over economy and ease of handling over the use of n-butyllithium.
Given that the conversion with potassium t-butoxide is inadequate, the use of it is not successful.

The novel formyloxy derivatives of formula (VI) are prepared by reacting the corresponding chloro derivative with formic acid in the presence of a base. Excess, eg 2-
Formic acid is neutralized using a 5-fold excess of formic acid with sufficient base. Although any salt may be used, organic bases such as triethylamine, dimethylaniline, pyridine and N-methylmorpholine are preferred. The reaction is carried out at about 0-10 ° C and the product is recovered by known procedures.

[0031] This serves as a useful intermediate for the preparation of compounds of the formula (I), and the reaction rate and (3 S, 4 R) -3- [1 (R) -t- butyldimethylsilyloxy ) Ethyl] -4-acetoxyazetidine-
The yield of 2-one is excellent.

The products of formula (I) is a 3 S, 4 R-4-substituted -3- [1 (R) -1- (dimethyl -t- butyldimethylsilyloxy) ethyl] azetidin-2-one ,
It is prepared by reacting racemic, cis or optically active forms of 3- [thio (thiocarbonyl) thio] thiolane-1-oxide in a reaction inert solvent.
By a reaction inert solvent is meant a solvent that reacts with the reactants or products to substantially reduce the yield of the desired product. Suitable 4-substituted azeticin-2-one reactants are those in which the 4-substituent is chloro, acetoxy, formyloxy or 2,4-dinitrophenylsulfonyl. Representative reaction-inert solvents are isopropyl alcohol and the neutral solvents listed below. The individual conditions for this reaction are the 4-fold of the azetidin-2-one reactant.
It was found to be affected to some extent by the substituents. In general, the preferred reaction-inert solvents are neutral solvents, such as acetone, methylene chloride, chloroform, tetrahydrofuran, ethyl acetate and mixtures thereof. The preferred neutral solvent is acetone. Reaction is about -1
It is carried out at 0 ° C to + 10 ° C for about 15 minutes to 2 hours.
Stoichiometrically equimolar amounts of reactants are required, but in excess, ie about 3-10% molar excess, of the appropriate 3- [thio (thio (thio) thiol salt, preferably the sodium salt. Carbonyl) thio] thiolane-1-oxide has proved to be practically advantageous.

The products of formula (I) are recovered in high yields and quality from reaction mixtures containing them by non-aqueous recovery conditions. The general procedure consists of quenching the reaction mixture with a neutral solvent or a mixture of neutral solvents and recovering the product, which is separated by filtration or centrifugation.

Considering that Compound (I) has poor stability under an aqueous recovery treatment as described above, the azetidin-2-one reactant in the above method is 3 R, 4 R -4-acetoxy-3. -[1 ( R ) -1- (dimethyl-t-butyldimethylsilyloxy) ethyl] azetidin-2-one, and the reaction inert solvent is isopropyl alcohol, the reaction mixture is methylene chloride / saturated. It was surprising to find that excellent quality product was obtained by quenching with aqueous ammonium chloride followed by concentration of the quenched mixture and addition of isopropyl ether to the concentrate.

[0035]

【Example】

Example 1 (3 R , 4 R ) -4-methylsulfonyl-3- [1
( R ) -t-Butyldimethylsilyloxy) ethyl]-
1- (1-methoxycarbonyl-2-methyl-1- pro
Propenyl) azetidin-2-one isomer methyl (3 S, 5 R, 6 S) -6- [1 (R)
-T-Butyldimethylsilyloxy) ethyl] penicillanate S, S-dioxide and methyl (3 S , 5
R, 6 R) -6- [1 (R) -t- butyldimethylsilyloxy) ethyl] Penishiraneto S, S- dioxide (34.9 g, in methylene chloride solution at ambient temperature containing 0.086 mol), 1,8-diazabicyclo [5.
4.0] Undec-7-ene (DBU 17.02 g, 1
12 mol) was added dropwise over 5 minutes. The reaction mixture was then stirred for 90 minutes, cooled to 0 ° C. and methyl iodide (53.5 g, 0.375 mol) was added over 10 minutes. Stirring was continued for 16 hours at 0 ° C. The reaction mixture was diluted with methylene chloride (200 ml) and adjusted to pH 3 water (2 x 40
0 ml), water (250 ml) and saturated NaHCO 3.
Washed with ₃ (250 ml). The organic extract is Na ₂ SO
_When treated with ₄ and the solvent was removed, 33.6 g
Viscous oil was obtained with a yield of 93%. IR (CHC
l ₃ ) 2953, 2930, 2887, 2857, 17
78, 1715, 1624, 1437, 1383, 13
21, 1144 cm- ¹ . NMR (250 MHz)
5.29 (d, J = 2.4 Hz, 1H), 4, 34 (d
q, 1H), 3.79 (s, 3H), 3.61 (dd,
J = 2.4 Hz, J = 3.1 Hz, 1H), 2.86
(S, 3H), 2.24 (s, 3H), 2.06 (s,
3H), 1.30 (d, J = 6Hz, 3H), 0.86
(S, 9H), 0.10 (s, 3H), 0.06 (s,
3H).

Calculated as C ₁₈ H ₃₃ NO ₆ SSi: C, 51.52; H, 7.93; N, 3.34; S, 7.64% Found: C, 50.52; H , 7.47; N, 3.14; S, 7.46%

[0037] Example 2 (3 R, 4 R) -3- [1 (R) -t- butyldimethylsilyloxy) ethyl] -4- methylsulfonyl azetidinone
2-one phosphate buffer (PH7,680ml), potassium permanganate (0.98 g, 0.006 mol), sodium periodate (87.3 g, 0.41 mol) and acetone (320 ml) Were combined at ambient temperature and cooled to 0 ° C. The unsaturated ester of Example 1 (33.6 g, 0.08 mol) in acetone (320 ml) was added over 8 minutes. The reaction mixture was stirred for 30 minutes at 0-5 ° C and then warmed to ambient temperature. The solution turned from purple to pink with a reaction time of 1 hour. 30 ml of aqueous potassium permanganate (15 g, 0.095 mol in 500 ml of water) was added. At 1 hour intervals, additional aqueous potassium permanganate was added in two portions (50 ml and 75 ml). The reaction was complete after 6 hours. Water (500 ml) and ethyl acetate were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 x 250 ml). The combined organic layers were washed with water (2 x 500 ml), dried over sodium sulphate and the solvent removed under vacuum to give 22.7 g (92%) of a viscous colorless oil. Crystals formed upon standing at 0 ° C .; melting point 10
1-102 ° C. IR (CHCl ₃ ) 3404, 295
0, 2930, 2886, 2856, 1793, 146
3,1321,1145,1128 cm < ^-1 >. NMR
(250 MHz) 6.53 (bs, 1H), 4.74
(D, J = 2.1 Hz, 1H), 4.32 (m, I
H), 3.56 (t, J = 2.5 Hz, 1H), 2.9
6 (s, 3H), 1.26 (d, J = 6Hz, 3H),
0.86 (s, 9H), 0.07 (s, 3H), 0.0
5 (s, 3H).

Calculated for C ₁₂ H ₂₅ NO ₄ SSi: C, 46.87; H, 8.20; N, 4.56; S, 10.43% Found: C, 46.83; H , 8.15; N, 4.33; S, 10.36%

[0039] Example 3 (3 R, 4 R) -4- (2,4- dinitrophenyl sulfonyl) -3- [1 (R) -t- butyldimethylsilyloxy) ethyl] -1- (1- Metokishikaru Bonil-2
-Methyl -1-propenyl) azetidin-2-one 25 g (61.7 mmole) of methyl 6- [1
( R ) -t-Butyldimethylsilyloxy) ethyl] penicillanate S, S-dioxide isomer mixture, 1
2 ml (80.6 mmole) of DBU, 12.5 g
(61.7 mmole) of 2,4-dinitrochlorobenzene and 138 ml of methylene chloride were used, except
The procedure of Example 1 was followed. After chromatography on silica with 20% ethyl acetate / hexane,
The title compound was obtained in 64% yield. MS m / e
514 (56), 340 (16), 288 (32),
281 (23), 207 (19), 182 (15), 1
58 (42), 73 (100). IR (CHCl ₃ ) 2
933, 2858, 1788, 1726, 1609, 1
545, 1464, 1437, 1352, 1305, 1
247, 1154, 1129, 1100, 1061 cm
^-1 . NMR (250 MHz) 8.65 (d, J = 2.
5Hz, 1H), 8.50 (dd, J = 2.5Hz, J
= 8 Hz, 1 H), 8.12 (d, J = 8 Hz, 1
H), 6.18 (d, J = 3 Hz, 1H), 4.39
(Bq, J = 3 Hz, 1H), 3.88 (t, J = 3H
z, 1H), 3.47 (s, 3H), 2.08 (s, 3
H), 2.06 (s, 3H), 1.30 (d, J = 7H
z, 3H), 0.82 (s, 9H), 0.10 (s, 3
H), 0.02 (s, 3H).

[0040] Example 4 (3 R, 4 R) -3- [1 (R) -t- butyldimethylsilyloxy) ethyl] -4- (2,4 Jinitorofe
Nylsulfonyl ) azetidin-2-one The unsaturated ester of Example 3 (20.25 g, 35.6 m)
mole) to carbon tetrachloride (81 ml), acetonitrile (81 ml), sodium periodate (15.22 g, 7)
1.6 mmole) and water (122 ml) at ambient temperature. To this two-phase solution, 500 mg of ruthenium trichloride was added to 25 ml of acetonitrile to obtain a solution of ruthenium trichloride trihydrate in acetonitrile (23.1).
ml) was added. After stirring for 4 hours, methylene chloride (2
00 ml) and a saturated aqueous solution of sodium hydrogen carbonate (2
00 ml) was added and the phases were separated. The aqueous phase is extracted again with methylene chloride (3 x 200 ml), the organic phases are combined,
Dry over magnesium sulfate and remove the solvent under vacuum. The oxamate salt product was a white solid (17.79).
g, 92%).

This oxidative cleavage can also be carried out using ozone as follows. A solution of unsaturated ester (0.2g) in methylene chloride (5ml) was cooled to 78 ° C. Ozone was bubbled through the solution until thin layer chromatography showed that all starting material had been consumed. Nitrogen was bubbled through this solution to remove excess ozone and dimethyl sulfide (1 m
1) was added and the flask was allowed to warm to ambient temperature with stirring for 1 hour. The organic phase was washed with water (20 ml), aqueous saturated sodium hydrogen carbonate (20 ml) and water (2 x 15 ml). After drying the organic phase with sodium sulphate and removing the solvent, 198 mg of the oxamate salt product was obtained as a white solid. NMR (250 MHz) 8.75 (d, J =
2.5Hz, 1H), 8.60 (dd, J = 2.5H
z, J = 8 Hz, 1H), 8.35 (d, J = 8 Hz,
1H), 6.29 (d, J = 3Hz, 1H), 4.54
(Dq, J = 7 Hz, J = 2 Hz, 1H), 4.09
(T, J = 2.5 Hz, 1H), 3.91 (s, 3
H), 1.40 (d, J = 7 Hz, 3H), 0.82
(S, 9H), 0.13 (s, 3H), 0.04 (s,
3H).

A solution of the oxamate salt (17.79 g) in tetrahydrofuran (360 ml) was added at ambient temperature to pH 7
Buffer (180 ml) was added. This solution for 18 hours,
Stir at ambient temperature. The solvent was removed under vacuum and ethyl acetate (250 ml) and saturated aqueous sodium hydrogen carbonate (250 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 250 ml). The combined organic extracts were dried over magnesium sulfate and the solvent removed under vacuum to give 12.1 g of crude title product. This material was purified by granulating with chloroform (15 ml) for 30 minutes. Filtration gave the product as a white solid (9.936g, 67%). The product was also obtained from the chloroform / hexane filtrate (450 mg), giving an overall yield of 70%; mp 14
8-149 ° C. NMR (250 MHz) 8.6-8.7
(M, 2H), 8.44 (d, J = 8Hz, 1H),
6.55 (bs, 1H), 4.36 (dq, J = 3H
z, J = 7 Hz, 1H), 3.85 (t, J = 3 Hz,
1H), 1.24 (d, J = 7Hz, 3H), 0.83
(S, 9H), 0.09 (s, 3H), 0.03 (s,
3H).

Example 5 (3 R , 4 R ) -4-formyloxy-3- [1 ( R )
-T-Butyldimethylsilyloxy) ethyl] azetidi
N-2-one triethylamine (21.12 ml) was stirred with formic acid (5.72 ml) in methylene chloride (80 ml).
The solution was added over 10 minutes at 10-12 ° C. The reaction mixture was then cooled to 0 ° C. and (3 R , 4 R ) -4-chloro-3- [1 ( R ) -t- in methylene chloride (80 ml).
Butyldimethylsilyloxy) ethyl] azetidine-2
-ON (8.0 g) was added dropwise at such a rate that the temperature did not exceed 1 ° C.

The reaction mixture was stirred for 1 hour at 0 ° C., the addition was completed and poured into pH 7 buffer (80 ml) to quench. Separate the methylene chloride layer and remove the pH 7.0 buffer (4x
80 ml), then dried (Na ₂ SO ₄ ),
Stripping under reduced pressure gave 5.4 g of the crude title product. This crude product was treated with 150 g of silica (70
Chromatography on -230 mesh) using ethyl acetate / hexane (20:80) as solvent system. Fractions of 800 drop volume were collected. 31-
The 75th fraction was combined and stripped to give 2.6 g of a white solid. Chromatography of this solid again under the same conditions gave 2.1 g (3
1%) of white crystalline product was obtained; mp 75-76.
° C.

[0045] EXAMPLE 6 3 S, 4 R -3- [ 1 (R) - ( dimethyl -t- butyl silyloxy) ethyl] -4- [cis-1-oxo -3
S-thiolanylthio (thiocarbonyl) thio] -2
Cis-3S in a 250 ml three-necked flask purged with dry nitrogen equipped with azetidinone mechanical stirrer, thermometer and dropping funnel.
-(Acetylthio) thiolane 1-oxide (11.4
g, 64.0 mmole) and 120 ml of isopropyl alcohol. It was cooled to −10 ° C. and sodium methoxide (3.71 g, 69 mmol).
e) was added over 2 minutes. After stirring at 0 ° C. for about 30 minutes, 17.5 ml of carbon disulfide was added. A slurry formed and was stirred for 1 hour. The reaction mixture was divided into two equal parts (one for treatment, the other for stability). 10.05 g (3
3 R, 4 R -4- acetoxy 5 mmole)-3-
[1 ( R )-(Dimethyl-t-butylsilyloxy) ethyl] -2-azetidinone was added to the reaction mixture at -15 ° C.
To -5 ° C over 22 minutes. The reaction mixture was then stirred and monitored by TLC (silica gel 9: 1 ethyl acetate / methanol). 30 reactions
It was judged that it was completed in a minute. The reaction mixture was concentrated under reduced pressure at -5 ° C to 5 ° C. The oil obtained was taken up in 50 ml of methylene chloride and the inorganic solids were filtered. The filtrate was concentrated again under reduced pressure, then the product was precipitated from methylene chloride / isobrolyl ether. The product was dried overnight in a vacuum oven without heating. Yield = 41%.

[0046] Example 7 (3 S, 4 R) -3- [1 (R) -t- butyldimethylsilyloxy) ethyl] -4- [1 (R) - oxo-3
S-thiol anilthio (thiocarbonyl) thio] aze
Cytidine 3-2-one 5.69g R, 4 R -4- formyloxy-3-
The procedure of Example 6 was followed, except that [1 ( R ) -t-butyldimethylsilyloxy) ethyl] azetidin-2-one was used in place of 4-acetoxyazetidin-2-one in the above example. .. The title product was recovered as a solid.

Similarly, the same product produces the following 4-substituted azetidin-2-one as a reactant:

[Chemical 20] _{Z = SO 2 [2,4- (NO} 2) 2 C 6 H 3] TBDMS = t- manufactured by using butyldimethylsilyl.

[0048] Example 8 (3 S, 4 R) -3- [1 (R) -t- butyldimethylsilyloxy) ethyl] -4- [1 (R) - oxo-3
S-thiol anilthio (thiocarbonyl) thio] aze
A Tidin-2-one three necked flask was equipped with a thermometer, magnetic stirrer and dropping funnel. It was purged with dry nitrogen and dissolved in acetone (35 ml) 3 R , 4 R -4-chloro-3-.
[1 ( R ) -t-Butyldimethylsilyloxy) ethyl] azetidin-2-one (3.8 g of 80% material, equal to 3.11 g of pure material) was charged. This solution-
Cooled to 2 ° C. and added sodium 3S- [thio (thiocarbonyl) thio] thiolane 1 R -oxide (3.409 g).
80% material, equal to 2.7 g of pure material) was added at once. The reaction mixture was stirred at −2 ° C. for 70 minutes, where methylene chloride (10 ml) was added and stirring was continued for 5 minutes. The salt that precipitated was filtered and washed with methylene chloride (5 ml). The filtrate and the washed liquid were combined and concentrated under reduced pressure. The obtained solid was a crude product with a theoretical yield of 88%. This solid was dissolved in methylene chloride (50 ml) and the solution was sodium sulfate (1 g) and activated carbon (0.
4g) for 10 minutes. The solution was then filtered and concentrated under reduced pressure to about 15 ml. Isopropyl ether (60m
l) was added dropwise to the concentrate to give a viscous slurry. After filtration, 3.53 g of the title product was obtained in 68% yield. An additional 1 g of product could be recovered from the mother liquor.

Example 9 1-N- (p-methoxyphenyl)-( 3S , 4R )-
3- [1 (R) - hydrin Rokishiechiru] -4- Fenirusu
Rufonylazetidin-2-one N- (p- in tetrahydrofuran (50 ml) at 0 ° C.
To methoxyphenyl)-(N-phenylsulfonylmethyl- (R) -glycidamide (3 g, 83 mM), N
NN'N'-tetramethylethylenediamine (3.8m
1, 25 mM) and lithium t-butoxide (2 g,
25 mM) was added. The reaction mixture was stirred at 0 ° C. for 3 hours, then diluted with ethyl acetate (250 ml).
5% hydrochloric acid (3 x 100 ml), water (1 x 100 m)
1) and brine (1 x 100 ml). The organic solvent mixture was dried (Na ₂ SO ₄ ) and stripped under reduced pressure to give 2.9 g of semi-crystalline product. When recrystallized from methanol, 1.65 g
Was obtained as a white solid; mp 191-
195 ° C. Yield = 55%.

Example 10 (3S, 4R) -3- [1 (R) -t-Butyldimethylsilyloxy) ethyl] -4- [1-oxo-3S-thiolanylthio (thiocarbonyl) thio] azetidine
-2-on 1435g (8.05mol) in a 50 gallon glass tank
Of sodium 3 S -acetylthiothiolane 1 R -oxide and 4.13 gallons of isopropyl alcohol (IPO) were charged and cooled to -5 ° C to 0 ° C. At this temperature, 473 g (8.67 mol) of sodium methylate were added and the reaction mixture was stirred for 35 minutes. This-
Cool to 10 ° C. and add 2.2 liters (37.5 mol) of carbon disulfide. The reaction mixture was stirred for 1 hour. (3
S, 4R) -4-Acetoxy-3- [1 (R) -t-butyldimethylsilyloxy) ethyl] azetidine-2-
A solution of on (2.56 kg, 1.1 eq) in methylene chloride (4.2 gallons) was prepared and added to the reaction solution over 25 minutes. The reaction mixture was stirred for 28 minutes (the reaction was monitored by TLC every 5 minutes and quenched as soon as the reaction was complete), which was then charged with 21 gallons of methylene chloride and 10.5 gallons of saturated ammonium chloride solution. Quenched by pouring into a containing tank. After performing the separation
Organic / product layer 12.2 gallons of 20% aqueous calcium chloride (6.38 kg) and 8.4 gallons of 50%
Wash with brine, then 8.3 gallons brine.
The organic layer was treated with activated carbon [319 g of Darco], dried over 3.2 kg of magnesium sulfate and then concentrated in vacuo to about 5 gallons. To this was gradually added 33.7 gallons of isopropyl ether. The resulting solid was stirred at -5 ° C to 0 ° C for 1 hour and filtered. The solid was vacuum dried at 25 ° C. and 2.21 kg of (3
S, 4R) -3- [1 (R) -t-Butyldimethylsilyloxy) ethyl] -4- [1-oxo-3-thiolanylthio (thiocarbonyl) thio] azetidine-2-
On was obtained in a yield of 62.5%. This was subjected to rotating high field NMR and HPLC analysis and found to be identical to this authentic sample.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Robert Wayne Dutger, Crest Drive, Misteit, Connecticut, USA 147 (72) Inventor, JOJO JOSEPH QUARICH, Northwestonton, Connecticut, USA 349 (54) Title of the Invention (3S, 4R) -3- [1 (R)-(t-butyldimethylsilyloxy) ethyl] -4- [1-oxo-3-thiolanylthio (thio Carbonyl) thio] azetidin-2-one and improved process for the preparation of intermediates therefor

Claims (18)

[Claims] 1. A compound of formula (VI): 2. Compound (a): Is isomerized to its trans form in the presence of a base and the trans form of the compound is represented by the general formula YZ, wherein Z is Cl, Br or I, Y is methyl or 2,4 -Dinitrophenyl) by reacting with a compound of formula (b): In the method for producing a compound of the formula (wherein Y is as described above), an improvement is that the isomerization step is performed using 1, as a base.
A method as described above, which comprises carrying out in the presence of 8-diazabicyclo [5.4.0] -undec-7-ene. 3. About 1.0-mole of the compound (a)
The method of claim 2, wherein about 2.0 equivalents of base are used. 4. The method of claim 3, wherein about 1.3 equivalents of base are used per mole of compound (a). 5. The method of claim 4, wherein YZ is methyl iodide. 6. The method of claim 4, wherein YZ is 2,4-dinitrochlorobenzene. 7. A compound of formula (d): embedded image in the presence of a base. By cyclizing a compound of formula (e) wherein Ar is an amino protecting group: In a method of making a compound of formula (wherein Ar is as described above), the improvement consists in cyclizing the compound of formula (d) with lithium t-butoxide in a solvent inert to the reaction. , Above method. 8. The molar ratio of lithium t-butoxide to the compound of formula (d) is about 1.1: 1 to 2: 1 and A
The method according to claim 7, wherein r is 4-methoxyphenyl or 3,4-dimethoxyphenyl. 9. The formula: (In the formula, Z is OCOCH ₃ , Cl, SO ₂ [ ₂ , 4-
The _{(NO 2) 2 C 6 H} 3] or -OCOH) compound, in an inert solvent in the reaction, the racemic cis - and optically formula including active form: embedded image By reacting with a compound of formula (I), including the racemic, cis- and optically active forms: In the method for producing the compound of
A method as described above, which comprises recovering the compound of claim 1 by performing a non-aqueous treatment. 10. The method according to claim 9, wherein the solvent inert to the reaction is a neutral solvent. 11. The method of claim 10, wherein Z is chloro and the neutral solvent is acetone. 12. The method of claim 11, wherein the reaction mixture is quenched with methylene chloride. 13. The method of claim 9, wherein the reaction inert solvent is isopropyl alcohol and Z is acetoxy. 14. The method of claim 13, wherein the reaction is quenched with acetone / methylene chloride. 15. The method of claim 14, wherein the quench is concentrated and treated with diisopropyl ether. 16. A compound of formula (I) including racemic, cis- and optically active forms. A method of preparing a compound of formula (A) in isopropyl alcohol: The compound of formula (B): A method as described above, which comprises recovering the product from the reaction mixture by reacting it with a compound of claim 1, sodium methylate and carbon disulfide and quenching the reaction mixture in methylene chloride / saturated aqueous ammonium chloride (2: 1). .. 17. A molar ratio of reactant (A) to reactant (B) to sodium methylate to carbon disulfide is about 1: 1:
The method of claim 16, wherein the ratio is from 1: 3 to about 1.1: 1: 1.1: 5. 18. The method of claim 17, wherein the product is recovered from the methylene chloride phase of the quenched reaction mixture by concentrating and adding isopropyl ether to the concentrate.