NO175368B - Intermediates for the preparation of therapeutically active diastereomers 5R, 6S-6- (1R-hydroxyethyl) -2- (cis-1-oxo-3-thiolanylthio) -2-penem-3-carboxylic acids - Google Patents

Description

Background for the invention

The present invention relates to intermediates for the production of antibacterial compounds which are diastereomeric 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acids.

Antibacterial 5R,6S-6-(1R-hydroxyethyl)-2-(cis-1-oxo-3-thiolanylthio)-2-penem-3-carboxylic acid which is a diastereomeric mixture of two compounds, has previously been discussed as a valuable antibacterial substance, by Hamanaka, US Patent 4,619,924 and European Patent Application 130,025. Although they have been able to be detected analytically, the pure diastereomeric compounds with the given structure have so far not been available. Disclosure of an improved process for the preparation of the diastereomeric mixture from racemic cis-3-(acetylthio)thiolane-1-oxide, which makes use of mixed diastereomeric intermediates which are otherwise analogous to those now used, will be found in a European patent application by Volkmann et al., calculated published on May 27, 1987 under No. 223,397.

With respect to the present optically active precursors, Brown et al., J. Am. Chem. Soc., vol. 108, pp. 2049-2054

(1986) described the synthesis of (S)-3-hydroxythiolane [mistakenly shown as the (R)-isomer, but in reality with the reverse configuration of the present (R)-3-hydroxythiolane of formula (XI) below] by asymmetric hydroboration of 2,3-dihydrothiophene. Partial Enzymatic Oxidation of Racemic 3-Hydroxythiolane by Jones et al., Can. J. Chem., vol. 59, pp. 1574-1579 (1981) made it possible to recover 3-hydroxythiolane containing a slight excess of the (R)-isomer. Present optically active precursor (R)-(2-methanesulfonyloxyethyl)oxirane [with the formula (XIII) indicated below where R<9> = CH3] and 2-bromo-1,4-di-(methanesulfonyloxy)butane [with the below indicated formula Xa, where R<8> = CH3] are known compounds both of which can be prepared according to Shibata et al., Heterocycles, vol. 24, pp. 1331-1346 (1986); the former also according to Boger et al., J. Org. Chem., vol. 46, p.

1208-1210 (1981).

According to parent application 89.0078 (patent 173.654), 5R,6S-6-(1R-hydroxyethyl)-2-(1R-oxo-3S-thiolanylthio)-3-carboxylates are prepared with the absolute stereochemical formula

wherein R is hydrogen or pivaloyloxymethyl, and the pharmaceutically acceptable cationic salts thereof when R is hydrogen. The present invention is directed to intermediates of the absolute stereochemical formula where R<6> is a conventional silyl protecting group; R<7> is hydrogen or

where R<10> is -CH2-CX=CH2, and X is hydrogen or chlorine.

Present compounds can be prepared via

(1) a method for preparing a compound of the absolute stereochemical formula

where. M<*> is an alkali metal cation, preferably Na<+>, comprising the following steps: (a) conversion of an epoxide with the absolute stereo chemical formula wherein R<9> is (C1-C1) alkyl, phenyl or p-tolyl, preferably methyl, by reaction with an alkali metal sulfide in a reaction-inert solvent, to form a compound of the absolute stereochemical formula (b) conventional sulfonylation of the compound of formula (XI) in a reaction-inert solvent, to form a compound of the absolute stereochemical formula wherein R<8 > is (C 1 -C 8 ) alkyl, phenyl or tolyl, preferably the latter; (c) conventional oxidation of the compound of formula (Xa) in a reaction-inert solvent, to form a compound of the absolute stereochemical formula (d) conventional nucleophilic displacement of R<8->SO2-0 in the compound of formula (Xb ) with an alkali metal thioacetate in a reaction-inert solvent, to form a compound with the absolute stereochemical formula

and

(e) conventional conversion of the compound of formula (VHIb) by means of CS 2 and an alkali metal alkoxide, preferably sodium ethoxide, in a reaction-inert solvent, to form the compound of formula (Villa); and

(2) an improved method for the preparation of a compound of the absolute stereochemical formula

where R<9> is (C 1 -C 8 ) alkyl, phenyl or p-tolyl, preferably methyl, comprising the following steps: (a) reacting a compound with the absolute stereochemical formula with Cs2C03 in a reaction-inert solvent, to form a compound of the absolute stereochemical formula

in higher stoichiometric step yields than 90%; and

(b) sulfonylation of the compound of formula (XV) with a sulfonyl chloride of formula

in the presence of a tertiary amine in a reaction-inert solvent, to form the compound of formula (XIII) in greater than 90% yield.

In this context, the term "reaction-inert solvent" refers to a solvent that does not react with starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.

Detailed description of the invention

The individual diastereomeric compounds according to the present invention can now be easily prepared. An important feature of the invention is the preparation of the optically active precursors with the above-mentioned formulas (VII) and (VIII) from known optically active compounds of formula (XII) and (XIII) respectively.

To prepare compound (Vila), the compound of formula (XII) is first reacted [known when R<8> = methyl; prepared analogously when R<8> is different from methyl] with an alkali metal sulfide (conveniently Na2S.9H2O) to form (S)-3-bromothiolane (IXa). At least one molar equivalent, usually a slight excess (e.g. 5-10%) of the sulphide salt is used together with a reaction-inert solvent, suitably an aqueous solvent, such as an aqueous (C 2 -C 3 ) alkanol (e.g . aqueous methanol) or aqueous acetonitrile. The temperature is not of decisive importance, 0-60°C is generally satisfactory. Room temperature, e.g. 17-28°C, is particularly suitable in that heating and cooling costs are avoided, although higher temperatures have the advantage of reducing the time required for completion of the reaction.

The intermediate bromothiolane (IXa) is then oxidized in a conventional manner to the S-oxide (IXb) by using approximately one molar equivalent of oxidant (usually in a slight excess to achieve complete mono-oxidation without substantial oxidation to the dioxide).

Suitable oxidants are m-chloroperbenzoic acid and potassium peroxy-monosulphate [KHS05. (KHSOJ 1/2. (K2S0A) 1/2] . The oxidation is carried out in a reaction-inert solvent, under which CH2C12 is particularly suitable for perbenzoic acid and acetone for peroxy-monosulphate. The temperature is not of decisive importance, e.g. temperatures generally satisfactory at -10 to 40° C. It is convenient to combine the reagents at a reduced temperature, eg 0-5° C, and then allow the reaction to proceed to completion at the above defined room temperature.

The sulfoxide intermediate (IXb) is then reacted with an alkali metal thioacetate under conventional nucleophilic displacement conditions to form 3R-(acetylthio)thiolane-1S-oxide (Vllb). Typically, an excess (eg, 1.5-2 molar equivalents) of the thioacetate salt is used in a reaction-inert solvent that allows significant concentrations of both reactants to drive this bimolecular reaction to completion within a reasonable amount of time. In the present case, acetone is a particularly suitable solvent. The temperature is not of decisive importance, thus e.g. 3 0-100°C is generally satisfactory, while the boiling point of the solvent acetone is particularly satisfactory.

Finally, the acetylthiolane (Vllb) is converted via the mercaptide salt (VII, Y = M<®>) to the trithiocarbonate salt (Vila). The intermediate mercaptide salt is generally formed in situ using an alkali metal alkoxide, usually in the corresponding alkanol as the reaction-inert solvent, sodium methoxide/methanol, sodium ethoxide/ethanol and sodium isopropoxide/isopropanol being all suitable for the purpose, usually at reduced temperature , e.g. -15 to +15°C, suitably close to 0°C. After it is formed, the mercaptide salt is usually reacted without isolation, with at least one molar equivalent of carbon disulfide (usually in excess, e.g. 3-5 molar equivalents), usually at an even lower temperature, e.g. -40 to 0°C, to form the desired 3R-(thio(thiocarbonyl)thio)thiolane-1S-oxide of formula (Via). The latter is isolated according to conventional methods or alternatively used in situ in the next process step.

To prepare the compound (Villa), the epoxide of formula (XIII) is first reacted [known when R<8> = methyl; in any case prepared according to the improved method described herein] with an alkali metal sulphide under the conditions described above for the conversion of (XII) to (IXa), in which case (R)-3-hydroxythiolane of formula ( XI). The latter is converted to the alkane, benzene or p-toluenesulfonate of formula (Xa) under conventional conditions, e.g. by using approximately one molar equivalent of the corresponding sulfonyl chloride, R<8>SO2C1, in the presence of at least one molar equivalent of a tertiary amine, preferably p-dimethylaminopyridine, in a reaction-inert solvent, such as methylene chloride, in a non- crucial temperature range of 0-50°C, appropriate at the room temperature defined above. The compound (Xa) is then oxidized to the sulfoxide (Xb), whereupon the sulfonate group is nucleophilically displaced with thioacetate to form 3S-(acetylthiothiolane-1R-oxide of formula (VHIb), hydrolyzed to the mercaptide (VIII, Y = M®) and finally reacted with CS2 to form the trithiocarbonate (Villa), all under the above conditions for the corresponding stepwise conversion of (IXa) to (Vila).

The present improved two-step process for the precursor (R)-(2-methanesulfonyloxyethyl)oxirane of formula (XIII) utilizes Cs2CO3 in a reaction-inert solvent (e.g., CH2Cl2) at room temperature [instead of refluxing aqueous NaOH according to Shibata et al ., cited above], whereby the compound (XIII) with significantly higher optical rotation is formed after conventional sulfonylation.

The second necessary precursor for the synthesis of the above compounds of formula (I) and (II) is 3R,4R-4-acetoxy-3-[1R-1-(silyl-protected hydroxy)ethyl]-2-azetidinone of formula

where R6 is a conventional hydroxy-protecting silyl group (preferably dimethyl-t-butylsilyl), a compound readily prepared from 6-aminopenicillanic acid, e.g. following the method of Leanza et al., Tetrahedron, vol. 39, pp. 2505-2513

(1983). In the next synthesis step, azetidinone is thus converted

(XVI) to the diastereoisomeric compound of formula (V) or (VI) where R<6> is hydrogen, by reaction respectively with the trithiocarbonate (Vila) or (Villa). With or without isolation of the trithiocarbonate, the reactants are combined in a reaction-inert solvent, such as a (C1-C3)alkanol, e.g. isopropanol, suitably in the solvent used for the preparation of the trithiocarbonate, in the presence of an excess of carbon disulphide (which may already be present in situ from the previous step). The reaction is generally carried out at a reduced temperature, e.g. ±2 0°C, appropriate at ice bath temperature (0-5°C) .

The compound of formula (V) or (VI) where R<7> is hydrogen is then reacted with an acid fluoride of formula

where R<10> is as defined above, to form the corresponding compound (V) or (VI) where R7 is -COCOOR<10.> This step is carried out in a reaction-inert solvent at 0° to -80°C in presence of a tertiary amine. Lower temperature, e.g. -3 0° to -7 0°C, preferred. A preferred reaction-inert solvent is methylene chloride. A preferred tertiary amine is N,N-diisopropylethylamine.

The necessary acid fluorides (XVII) are prepared from the corresponding acid chlorides using reagents previously used for this purpose, either anhydrous cesium fluoride (usually at or near room temperature, with reagents that are initially combined at low temperatures, e.g. 0 ° to -30°C) or potassium fluorosulfinate (FS02K, usually at somewhat higher temperatures, e.g. 40-85°C). The latter reagent and reaction conditions are preferred when R<5> is pivaloyloxymethyl.

As for other necessary starting materials for the preparation, 3R,4R-4-acetoxy-3-[1R-1-(silyloxy)ethyl]-2-azetidinones are readily available by the method of Leanza et al., cited above. Allyl oxalochloride is available by the method of Afonso et al., J. Am. Chem. Soc, vol. 104, pp. 6138-6139 (1982); 2-Chlorallyl oxalochloride is available from 2-chloroallyl alcohol and oxalyl chloride by the method described in more detail below, and pivaloyloxymethyl oxalochloride is prepared over several steps from the benzyl half-ester of oxalic acid and chloromethylpivalate, also described in more detail below.

The following examples are given by way of illustration and are not to be understood as limitations of the invention, as a number of variations of these fall within the scope of the invention.

Example 1

( R )- 3- hydroxythiolane ( XI )

In a dry flask, 19.62 g (0.118 mol) of (R-(2-methanesulfonyloxyethyl)oxirane was dissolved under N 2 in 600 mL of acetonitrile and 100 mL of water. Sodium sulfide (18.67 g, 0.239 mol) was added and the reaction mixture stirred at room temperature for 24 hours. The two layers were separated and the aqueous layer extracted with methylene chloride (3 x 15 mL). The combined organic layers were washed with 1N sodium hydroxide. The aqueous layer was extracted with methylene chloride (3 x 150 mL), salted with NaCl and extracted with more CH 2 Cl 2 (2 x 100 mL). The organic layers were combined, washed with 50 mL 1N NaOH, 50 mL saturated NaCl, dried (MgSO 4 ) and evaporated to give the title product, 11.05 g (90% step -yield, 90% total yield from S-2-bromo-1,4-butanediol);

[α]D = +13.93° (c = 1.4, CHCl 3 ); pnmr (CDC13) delta (ppm) : 1.70-1.90 (1H, m, CH), 2.00-2.18 (2H, m, CH, OH), 2.70-2.98 (4H , m, CH 2 S), 4.50-4.52 (1H, m, CHO). For the corresponding S-isomer, Brown et al., J. Am. Chem. Soc, vol. 108, p. 2049

(1986) stated [a]D<25> = -14.5° (c = 1, CHCl3).

Example 2

(R)- 3-(p-toluenesulfonyloxy)thiolane (Xa, R<8> = p- tolvl)

In a flame-dried flask, 11.03 g (0.106 mol) of (R)-3-hydroxythiolane was dissolved under nitrogen in 150 ml of dry methylene chloride and cooled to -5°C. To this was added 25.88 g (0.212 mol) of 4-dimethylaminopyridine and 20.19 g (0.106 mol) of p-toluenesulfonyl chloride and the mixture was stirred at room temperature for 60 hours. It was then washed with 1N hydrochloric acid (25 mL), the washings extracted with methylene chloride (3 x 50 mL), the combined organic layers washed with brine, dried (MgSOA) and evaporated to dryness to give 34.73 g of crude product. This was filtered through a layer of silica gel (13 cm diameter, 10 cm depth) eluting with 1:5 ethyl acetate:hexane and then with ethyl acetate alone. Product-containing fractions were combined and evaporated to give 21.52 g (79%) of purified product; [a]D = +16.76°

(c = 2.98, CHCl 3 ); pnmr (CDC13) delta (ppm) : 1.76-1.90 (1H, m, CH) , 2.12-2.26 (1H, m, CH) , 2.40 (3H, s, CH3) , 2.70-3.00 (4H, m, CH2S), 5.13-5.16 (1H, m, CHO), 7.25 (2H, d, CH), 7.74 (2H, d, CH ).

Example 3

3R-(p-toluenesulfonyloxy)thiolane 1R-oxide (Xb, R<8> = tolyl)

A solution of 46.30 g (0.179 mol) of 3R-(toluene-sulfonyl-oxy)thiolane in 600 ml of acetone was cooled under nitrogen to 0°C. In a separate flask, 61.73 g (0.100 mol) of potassium peroxymonosulfate (2KHSO5.KHSO4.K2SO,,;) was stirred into 500 ml of distilled water until the solution became clear. It was added to the acetone solution at 0°C, after which the mixture was allowed to reach room temperature. After 25 minutes, 75 ml of 10%

(w/v) aqueous sodium sulfite, the acetone was evaporated, 300 mL of ethyl acetate was added, and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried (MgSOJ) and concentrated to dryness to give 48.57 g of crude product. The latter was purified by chromatography on silica gel using 10:10:1 ethyl acetate:CH2Cl2:CH3OH as eluent to give purified title product, 34, 67 g (71%); [α]D = +4.26° (c = 3.0, CHCl 3 ).

Example 4

3S-(acetvltio)thiolane-lR- oxvd fVIIIb)

In a flame-dried flask, 31.67 g (0.1156 mol) of 3R-(p-toluenesulfonyloxy)thiolane-1R-oxide was dissolved in 300 ml of acetone under nitrogen and 19.81 g (0.1734 mol) of potassium thioacetate was added. The mixture was refluxed for 3.5 hours and stirred at room temperature overnight. The mixture was filtered, purified and washed with 500 ml of acetone, whereupon the filtrate and washings were evaporated in vacuo to give 23.96 g of the desired product as an oil. The oil was purified by flash chromatography on a 120 mm x 25 cm silica gel column eluting with 19:1 ethyl acetate:methanol collecting 125 ml fractions. Fractions 42-64 were combined and evaporated to give purified title product as an oil which crystallized on standing, 16.46 g; (80%); m.p. 51-52°C; [α]D = -83.41° (c = 0.86, CHCl 3 ). Analysis calculated for C6H10S2O2:

Calculated: C, 40.4; H, 5.6%.

Found: C, 40.15; H, 5.53%

Example 5

Sodium- 3S-( thio( thiocarbonyl) thio) thiolane- 1R- oxvd ( VTIIa, = Na<@>)

In a flame-dried flask, a solution of 1.78 g

(10 mmol) 3S-(acetylthio)thiolane-1R-oxide in 6 ml of ethanol under nitrogen cooled to -5°C. Sodium ethoxide (21% by weight in ethanol, 3.73 mL, 10 mmol) was added and the mixture stirred at

-5°C for 30 minutes, then cooled to -20°C, whereupon 3.0 mL (50 mmol) of carbon disulfide was added and stirring continued for 30 minutes. To this was added 75 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred for a few minutes, seeded with crystals of the title compound, cooled and kept at 15°C and stirred until crystallization was complete. The mixture was filtered, washed with cold tetrahydrofuran and then with ethyl ether. The resulting crystals were air-dried under nitrogen to give 2.10 g of the title product solvated with 0.5 molar equivalents

tetrahydrofuran. A further 592 mg was recovered by working up the mother liquor; m.p. 120-121°C (decomp.), blackens at 155-156°C; [o]D = -79.52° (c = 0.05, in H 2 O).

Example 6

3S,4R-3-[1R-1-(dimethyl-t-butylsilyloxy)ethyl]-4-[1R-oxo-3S-thiolanylthio(thiocarbonyl)thio]- 2- azetidinone ( VI, R<7>-H, R6=Me, tBuSi)

In a flame-dried flask, a solution of 3R,4R-4-acetoxy-3-[IR-(dimethyl-t-butylsilyloxy)ethyl]-2-azetidinone [1.87 g, 6.5 mmol; Leanza et al., Tetrahedron 39, pp. 2505-2513

(1983)] in 20 mL of isopropyl alcohol and CS2 (0.15 mL, 2.5 mmol) combined under nitrogen and cooled to 3°C. The product from the previous example (1.36 g, 5 mmol) was added portionwise during which the temperature was maintained at 3°C. After 0.5 hours at 3°C, the reaction was quenched with 40 ml of saturated ammonium chloride solution and 50 ml of ethyl acetate was then added to the mixture. The organic layer was separated and the aqueous layer extracted with an additional 2 x 25 mL of ethyl acetate. The combined ethyl acetate layers were washed 2 x 20 mL H 2 O and 2 x 20 mL 20% CaCl 2 , dried over MgSO 4 , filtered and concentrated in vacuo to give the crude title product, 3.04 g. The latter was dissolved in ca. 2 ml of acetone and isopropyl ether added dropwise until precipitation of solids started, after which the mixture was stirred for 1 hour and then, while stirring, quickly added 120 ml of petroleum ether. The resulting solid was filtered off, air dried, then dried in vacuo and finally chromatographed on silica gel using 19:1 ethyl acetate:methanol as eluent to give 1.35 g (61%) of purified title product. Recrystallization from 4 ml of acetone following the same procedure gave 1.15 g of product; [a]D = +109.36° (c = 0.20, CHCl 3 ), pnmr (CDC 13 )

(delta) (ppm) 300 MHz: 0.05 (s, 3H), 0.86 (s, 9H), 1.18 (s, 3H) , 1.74 (s, 2H) , 2.68 (m , 3H) , 2.82 (m, 1H) , 3.17 (m, 2H) , 3.74 (q, 1H), 4.25 (t, 1H), 4.52 (t, 1H), 5 .61 (s, 1H), 6.52 (s, 1H), 7.20 (s, 1H).

Example 7

3S,4R-N-[(2-chloroallyloxy)oxalyl]-3-[IR-(dimethyl-t-butylsilyl-oxy)ethyl]-4-[1R-oxo-3S-thiolanylthio(thiocarbonyl)thio]-2-

azetidinone fVI. R6=Me, tBuSi. R7=C0C00CH, CC1CH,)

A flame-dried, three-necked flask fitted with a dropping funnel and a low-temperature thermometer was added under an N2 atmosphere to the product from the preceding example (878 mg,

2 mmol) and 15 ml of dry methylene chloride (passed through neutral alumina). The reaction mixture was cooled to -50° to -55°C internal temperature and N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) was added, maintaining the temperature below 50°C. Then 2-chloroallyl oxalofluoride (0.34 ml,

2.6 mmol) was added as quickly as possible, during which the temperature was again kept below 50°C, and the reaction mixture was stirred for another 50 minutes at -50° to -55°C. The reaction was quenched with 15 ml of H 2 O, after which the mixture was allowed to warm to 0°C and was diluted with 20 ml of fresh CH 2 Cl 2 . The organic layer was separated, washed 1 x 15 mL H 2 O, 1 x 20 mL pH 7 buffer and 1 x 25 mL saturated NaCl, dried over MgSO 4 , filtered and concentrated in vacuo to give 1.05 g of the title product as a yellow foam, which was used in its entirety directly in the next step.

Production 1

2-chloroallyl oxalofluoride-[(2-chloroallyloxy)oxalyl fluoride]

CH ?=CC1CH-, Q f CO) COF

Under dry N2 and using flame-dried glassware, cesium fluoride (167 g, 1.1 mol) was placed in a 1 L round bottom flask which was placed under high vacuum and gently heated with a flame until the solid became free-flowing and then cooled to room temperature. Acetonitrile, distilled from CaH 2 (18 3 mL) was added and the mixture cooled to -20°C internal temperature. 2-Chloroallyl oxalochloride (183 g, 1.0 mol) was added dropwise over 30 minutes and the mixture slowly warmed to room temperature, stirred at this temperature for 16 hours and the by-product cesium chloride filtered off and washed with acetonitrile. Filtrate and wash were combined and evaporated and the residue distilled at reduced temperature to give 129 g (77%) of the desired product, b.p. 62-64°C/22 mm.

IR (CHCl 3 ) cm"<1> 1770, 1870.

<X>H-NMR (CDCl 3 ) delta (ppm) 4.80 (s, 2H), 5.4-5.6 (m, 2H).

Manufacturing 2

Allyl oxalofluoride

[Allyl oxalyl fluoride]

CHo=CHCH?0 ( CO)COF

Following the procedure of the preceding preparation, allyl oxalochloride (252.5 g, 1.70 mol) and cesium fluoride (284 g, 1.87 mol) were converted to the title product which was distilled twice, b.p. 48-50°C/35mm;

124-126°C (atmospheric pressure).

<1>H-NMR (CDCl3) 250 MHz, delta: 4.76 (d, 2H, J=6Hz), 5.28 (dd, IH, J=1, 7Hz), 5.37 (dd, 1H, J=1, 17Hz), 5.90 (ddt, 1H, J=6, II, 17Hz).

<13>C-NMR (CDCI3) 63 MHz, delta: 68.5 (t) , 120.4 (t) , 129.7 (d) , 146.3 (d, Jc_F=375Hz) , 153.0 ( d, Jc.c_F=87Hz) .

IR (undiluted) 1860 (C=0) , 1770 (C=0) , 1120 cm"<1>.

Manufacturing 3

2-chloroallyl oxalochloride

f(2-chloroallyloxy)oxalyl chloride Oxalyl chloride (130 mL, 1.49 mol) was placed in a dry three-necked flask under N 2 and cooled to 0°C. While stirring, 2-chloroallyl alcohol (138 g, 1.49 mol) was added dropwise in such a way that the temperature was maintained at 0-2°C and the vigorous HCl evolution was controlled, whereupon the mixture was allowed to assume and was held at room temperature for 16 hours and was distilled to give the title product, 214 g, b.p. 82-84°C/23 mm.

Manufacturing 4

( S)- 2-bromosuccinic acid

To a solution of 1.000 g (9.72 mol) of sodium bromide in 2.1 liters of 6N sulfuric acid, 323.1 g (2.43 mol) of L-aspartic acid was added under nitrogen and the resulting solution cooled to 5°C. 201.4 g (2.92 mol) of sodium nitrite were added in portions over the course of 1.5 hours, during which the temperature was kept lower than 10°C. After the addition was complete, 1 liter of distilled water was added, then 73.07 g (1.22 mol) of urea. The resulting mixture was poured into a separatory funnel and extracted with 2.5 liters of ethyl ether. To the aqueous layer was added 500 g of sodium chloride and the mixture was extracted three times with ether (3 x 1.25 liters). The combined ether layers were washed with brine, dried (Na 2 SO 4 ) and the solvent evaporated in vacuo to give 303 g (63%) of the desired compound; [α]D = -73.5° (c = 0.6 in ethyl acetate); m.p. 185°C.

Manufacturing 5

( S )-2-bromo-1, 4-butanediol

Using flame-dried glassware under nitrogen, 303.14 g (1.54 mol) (S)-2-bromosuccinic acid was dissolved in 3.2 liters of anhydrous tetrahydrofuran (THF) and the mixture cooled to -20°C. A solution of 350.78 g of borane-methyl sulphide complex in 438 ml of tetrahydrofuran (4.62 mol) was added dropwise over the course of 90 minutes. The mixture was stirred while slowly heating to 18°C, whereupon the reaction mixture released hydrogen gas and became exothermic. The mixture was cooled in dry ice/acetone while nitrogen was introduced over the mixture. After 15 minutes, the cooling bath was removed, whereupon the reaction mixture was allowed to reach room temperature and kept under a stream of nitrogen for 60 hours. 1 liter of methanol was slowly added and the nitrogen purge continued for 30 minutes, after which the solvents were evaporated. The residue was taken up in 1 liter of methanol and the solvent evaporated again. This was repeated two more times to obtain 282.41 g (100%) of the desired diol.

Manufacturing 6

(R)-(2-methanesulfonyloxyethyl)oxirane

A. Using dry glassware under nitrogen, 20 g (0.118 mol) of (S)-2-bromo-1,4-butanediol was dissolved in 400 ml of dry methylene chloride and 69.41 g (0.213 mol) of cesium carbonate was added. The mixture was stirred at room temperature for 40 hours and then filtered and washed with CH 2 Cl 2 . Filtrate and washing liquid were combined and used directly in part B below. If desired, the solvent was evaporated to give the intermediate (R)-(2-hydroxyethyl)oxirane in practically quantitative yield.

B. In a flame-dried flask under nitrogen, the entire product solution from part A (ca. 800 mL) was added and then cooled to -25°C. Triethylamine (21.55 g, 0.213 mol) was added followed by the slow addition of 20.34 g (0.178 mol) of methanesulfonyl chloride over 25 minutes, during which the temperature was maintained below -20°C. The resulting mixture was allowed to reach room temperature over 1.5 hours, extracted 1 x 50 ml pH 4 buffer and the buffer solution extracted 3 x 50 ml CH 2 Cl 2 . The organic extracts were combined with the original organic layer, extracted 1 x 50 ml saturated NaCl, and the brine extracted with 3 x

50 mL of CH 2 Cl 2 , whereupon the organic extracts were combined with the original organic layer, which was evaporated to give the title product in approximately quantitative yield; [a]D = +34.7°

(c = 0.1 in CH 2 Cl 2 ); pnmr (CDC13) delta (ppm) : 1.76-1.85 (1H, m, CH), 2.02-2.11 (1H, m, CH), 2.50-2.52 (1H, m , CHO), 2.77-2.80 (1H, m, CHO), 2.98-3.04 (1H, m, CHO), 2.99 (3H, s, CH3) , 4.32 (2H , t, CH 2 O) .

Claims (2)

1. Connection characterized in that the absolute stereochemical formula: wherein R 6 is a conventional silyl protecting group; R 7 is hydrogen or X is hydrogen or chlorine. 2. Compound according to claim 1, characterized in that R is dimethyl (t-butyl)silyl and R<7> is hydrogen or -C-C-OR<10> where R<10> is 0 0