HU187175B - Process for producing new azetidione derivatives substituted withcyanomethyl group - Google Patents

Abstract

The present invention relates to a process for the preparation of novel compounds of formula VI, wherein R * is phenyl or benzyl optionally substituted with one or more methoxy groups, such that a compound of formula V wherein R1 is as defined above and has halogen atoms \ t , with an alkali metal cyanide. The new compounds produced are intermediates in the production of thienamycin. -1-

Description

This invention relates to novel compounds of formula VI. In this formula

R ^{1 is} optionally substituted by one or more methoxy-substituted phenyl or benzyl.

The novel compounds produced are useful in the manufacture of (±) -thienamycin and related compounds as simple and economically obtainable intermediates.

Thienamycin is a broad-spectrum antibiotic, the microbiological preparation of which is disclosed in U.S. Patent No. 3,950,357, and its synthesis, which is initiated in a yield below 10%, is disclosed in U.S. Patent No. 2,751,597.

It has now been found that compounds of Formula VI can be prepared by reacting a compound of Formula I, wherein R ¹ is the same as Formula VI and Z is a C 1 -C 4 alkyl, with an acylating derivative of haloacetic acid. The compound of formula II, wherein R ¹ and Z are as defined above and X is halogen, is cyclized to the compound of formula III in the presence of an acid-binding, preferably tertiary amine. In formula III, R ¹ and Z are as defined above. The compound of formula III is then reacted with an alkali metal halide in pyridine or in aqueous dimethylsulfoxide. The reaction results in a compound of Formula V wherein R ¹ and Z are as defined above.

The compound of Formula IV is then first reduced with a complex metal hydride to a compound of Formula V having M at the hydroxy group (R ¹ is as defined above), followed by reacting the resulting compound with alkanesulfonic acid halide or arenesulfonic acid halide on cooling. wherein M is -O-SO ₂ -R ² (R ² = C 1 -C 4 alkyl or aryl) and R ¹ is unchanged. The resulting compound is then reacted with an alkali metal halide to give the halogen at M

Compound V (R ¹ is unchanged).

If M contains a hydroxyl group

Reaction of the compound of formula V in the presence of a tertiary amine with an alkane or arenesulfonic acid halide at elevated temperature yields a compound of formula V directly having M as halogen.

The novel compounds of formula V, which are starting materials for the process of the present invention, are protected by separate application.

The present invention relates to a process for the preparation of new compounds of formula VI, wherein R ^{1 is} phenyl or benzyl optionally substituted with one or more methoxy groups, by reacting a compound of formula V wherein R 'is as defined above and M is halogen - reacted with an alkali metal cyanide.

Sodium or potassium cyanide are used as reagents in the process of the invention. The reaction is conveniently carried out in a dipolar aprotic solvent, preferably dimethylformamide.

The following examples are intended to illustrate the process, but are not intended to limit the scope of the examples.

Example 7

4- (Cyanomethyl) -T (2,4-dimethoxybenzyl) -2-azetidinone

A solution of 1.2 g (3.3 mmol) of 1- (2,4-dimethoxybenzyl) -4- (iodomethyl) -2-azetidinone in 5 mL of dimethylformamide was stirred with 0.35 g (7 mmol) of sodium cyanide at room temperature. hours. The solution was then poured into water (30 mL) and extracted with ether (5 x 20 mL). After drying over anhydrous magnesium sulfate, the ethereal solution was clarified with activated carbon, filtered and the filtrate was concentrated in vacuo. Yield: 0.6 g (70%) of the title compound. Elemental analysis for C ₁₄ H, _Ö N ₂ O ₃ (260.3):

Calculated: N, 10.76;

Found: N, 10.71;

IR (film): 2920; 2270; 1750 cm '.

The starting material of the example is prepared as follows:

a) 50 g (0.30 mol) of 2,4-dimethoxybenzaldehyde

Benzylamine (34.4 mL, 33.6 g, 0.31 mol) in anhydrous toluene (300 mL) in the presence of 1 g of p-toluenesulfonic acid was refluxed for 8 hours while the resulting water was continuously removed with a water separator. The toluene is then distilled off. The resulting oil was dissolved in dioxane (120 mL) and treated with 3.2 g of sodium [tetrahydroborate (III)] under cooling with external ice-water and stirring for 2 hours.

The reaction mixture was allowed to stand for 3 days and then

The reaction mixture was diluted with 400 ml of water, the resulting oil was extracted with ether, dried over magnesium sulfate, filtered and the filtrate was concentrated to half. Then, while cooling with ice-water, hydrochloric ethanol was added dropwise to the ethereal solution.

Yield: 59 g (67%) of benzyl (2,4-dimethoxybenzyl) amine hydrochloride.

156-157 ° C (ethyl acetate)

Elemental analysis for C, _e H _{2 O} CINO ₂ (293.78):

calculated%:

C, 65.41; H, 6.86; Cl, 12.07; N, 4.77;

Cnfalt *

C 65 ° 63; H, 7.30; Cl, 11.69; N, 4.72.

b) The base of the product obtained in Example 1a) is liberated and the resulting benzyl (2,4-dimethoxybenzyl) amine (175 g, 0.68 mol) is 89.6 g (0.38 mol; 64 ml). ) with diethyl bromo malonate at room temperature until the reaction mixture thickens. The solidified mixture is then cooled for approx. Triturate with 1 L of ether and filter the precipitated crystals. (so that excess starting amine in the form of the hydrobromide can be recovered in about 95% yield). The filtrate was evaporated and the residual oil was triturated with ethanol.

Yield: 114.5 g (81%) of diethyl [N-benzyl-N- (2,4-dimethoxybenzyl) aminophosphate]

187,175

Mp 62-63 ° C (ethanol)

Elemental analysis for C ₂₃ H ₂₉ NO ₆ (415.47):

Found: C, 66.49; H, 7.04; N, 3.37. Found: C, 66.58; H, 7.09; N, 3.43.

IR (KBr): 1750/1725 cm -1, d

c) diethyl [N-benzyl-N- (2,4-dimethoxybenzyl) amino malonate] (61.7 g, 0.149 mol), prepared in Example 1b), was dissolved in ca. Hydrogenation is carried out under atmospheric pressure in the presence of 20 g of palladium on charcoal in 500 ml of ethanol. The catalyst was filtered off and the filtrate was evaporated.

Yield: 47.1 g (97%) of diethyl [N- (2,4-dimethoxybenzyl) amino-malonate]; optionally converting it to the acid addition salt with hydrochloric acid.

HCl salt: mp 122-124 'C (EtOAc)

Elemental analysis for C ₁₆ H ₂₄ ClNO ₆ (361.82):

calculated%:

C, 53.11; H, 6.69; Cl, 9.80; N, 3.87. found *

C 52.51; H, 6.77; Cl, 10.30; N, 4.09.

IR (film): 3250, 2900, 2850, 1730, 1720 cm -1. 1 H-NMR (CDCl ₃ ):

δ 1.3 t (6H); 3.78 s (3H); 3.82 s (3H);

4.21 q (4H); 6.20 s (2H); 6.4-6.6 m (2H) + 7.3-7.55 m (1H); 7.7 s (1H).

d) 47 g (0.144 mol) of diethyl [N- (2,4-dimethoxybenzyl) aminomalonate] prepared in Example le) in 200 ml of anhydrous benzene 13.8 ml (19.6 g; (0.173 mol) of chloroacetyl chloride was refluxed for 3.5 hours. The benzene is distilled off and the residual oil is distilled off for about 30 minutes. Recrystallize from 100 ml of ethanol.

Yield: 66% diethyl [N- (2,4-dimethoxybenzyl) -N (chloroacetyl) amino malonate].

M.p. 83-84 C (ethanol).

Elemental analysis for C ₁₈ H ₂₄ ClNO ₇ (401.84):

calculated%:

C, 53.80; H, 6.02; Cl, 8.82; N, 3.49; found %:

C, 53.63; H, 6.26; Cl, 8.79; N, 3.56.

IR (KBr): 2920; 1755, 1680 cm ^-1 .

1 H-NMR (CDCl ₃ ):

δ 1.2 t (6H); 3.72 s (6H); 4.08 q (4H);

4.17 s (2H); 4.56 s (2H); 4.95 s (1 H);

6.2-6.6 m (2H) + 6.95-7.25 m (1H).

e) 35 g (0.087 mol) of diethyl [N- (2,4-dimethoxybenzyl) -N- (chloroacetyl) amino malonate] prepared in Example 1d (15.9 ml). Triethylamine (4 g, 0.113 mol) in anhydrous benzene (200 ml) was refluxed for 8 hours. The mixture was partitioned between water (100 ml), dilute hydrochloric acid (100 ml) and water (100 ml) again, the benzene layer was dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 28.4 g (89%) of diethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidinedicarboxylate].

Mp: 175-180 ° C (0.1 mm Hg).

Anal calcd for _{C] 8} H ₂₃ NO ₇ (365.68):

Found: C, 59.17; H, 6.34; N, 3.83; Found: C, 59.24; H, 6.24; N, 3.54.

IR (KBr): 2900; 1760-1720 ^cm-first

1 H-NMR (CDCl ₃ ):

δ 1.15 t (3H); 1.25 t (3H); 3.25 - s (2H);

3.7 s (6H); 3.8 ^ 1.25 m (4H); 4.50 s (2H);

6.3 m (2H) + 7.0 d (1H).

f) Diethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azaethidinedicarboxylate] (66.2 g, 0.18 mol) prepared in Example le) in dimethyl sulfoxide in the presence of 12.7 g (0.22 mol) of sodium chloride and 6.5 ml (0.36 mol) of water in an oil bath at 170-180 ° C for 6 hours. The mixture was poured into 500 ml of a saturated aqueous sodium chloride solution, extracted with ethyl acetate (5 x 100 ml), the organic phase was dried over magnesium sulfate, filtered and the ethyl acetate was distilled off from the filtrate.

Yield: 47.6 g (90%) of ethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2,2-azetidine carboxylate].

Mp: 170-176 ° C (0.15 mm Hg).

Elemental analysis for C ₁₅ H ₁₉ NO ₅ (293.32):

Found: C, 61.42; H, 6.53; N, 4.77; Found: C, 61.25; H, 6.87; N, 4.58.

IR (film): 2900; 1750-1725 cm -1.

g) Ethyl [1- (2,4-dimethoxybenzyl) -4-oxo-2-azetidinecarboxylate] prepared in Example 1f (47.6 g, 0.162 mol) in methanol (200 ml), cooled with ice-cold water. while reacting with 12.4 g (0.327 mol) of sodium telhydride borate (II). The reaction was carried out for ca. in half an hour. The solution was neutralized with dilute hydrochloric acid and the methanol was distilled off and the oil precipitated from the aqueous mixture was extracted with ethyl acetate (5 x 50 ml).

The ethyl acetate layer was dried over magnesium sulfate, filtered and the filtrate was evaporated. Yield: 39.1 g (96%) of 1- (2,4-dimethoxybenzoyl) -4-hydroxymethyl-2-azetidinone.

IR (film): 3350; 2900; 1750-1700 cm '.

1 H-NMR (CDCl ₃ ):

<5 2.1 s (1H); 2.85 m (2H); 3.65 m (2H);

3.82 s (3H); 3.85 s (3H); 4.05 m (1H);

6.38 s (2H); 6.55 m (2H) + 7.25 d (1H).

h) 39.1 g of a solution of 1- (2,4-dimethoxybenzyl) -4- (hydroxymethyl) -2-azetidinone prepared in Example 1g in 100 ml of pyridine under cooling with external ice-water are treated with 15.3 ml of Mesyl chloride (23.6 g, 0.206 mol) was added dropwise, and the mixture was stirred until the starting material was completely complete (about 2-3 hours). The mixture was poured into 500 ml of water. The precipitated oil crystallizes slowly.

Yield: 37.5 g (73%) of 1- (2,4-dimethoxybenzyl) -4-mesyloxymethyl-2-azetidione.

M.p. 71-72 'C (ether)

Elemental analysis for C ₁₄ H ₁₉ NO ₆ S (329.36):

calculated%:

C, 51.05; H, 5.81; N, 4.25; S, 9.74; found /'

C 51 ° 19; H, 6.07; N, 4.19; S, 9.93.

IR (KBr): 1735 cm -1.

i) 1- (2,4-Dimethoxybenzyl) -4- (mesyloxymethyl) -2-azetidinone (37.5 g, 0.107 mol) prepared in Example 1h in 250 ml of anhydrous acetone. moles) of sodium iodide was refluxed for 8 hours. An additional 18.8 g (0.125 mol) of sodium iodide was added and the mixture was refluxed for a further 8 hours. The mixture was evaporated to dryness in vacuo from a 50 'C water bath, then triturated with 100 ml of water and 100 ml of dichloromethane.

Extract with 187 175 methane. The aqueous phase is extracted with three further 50 ml portions of dichloromethane. The combined dichloromethane solution was dried over magnesium sulfate, filtered and the filtrate was evaporated. Yield: 40.3 g (98%) of 1- (2,4-dimethoxybenzyl) -4-iodomethyl) -2-azetidinone.

IR (film): 2920; 1750 cm ^-1 .

Example 2

4- (Cyanomethyl) -1-phenyl-2-azetidinone g (3.5 mmol) 1-phenyl-4- (iodomethyl) -2-azetidinone In 5 mL dimethylformamide 0.4 g (8 mmol) sodium -. with cyanide for 24 hours at 0 ° C. ¹ the mixture was poured into 20 mL of saturated aqueous sodium chloride solution in ether and extracted three times with 30 ml. The ether solution was dried over anhydrous' magnesium sulfate, filtered, and the filtrate was evaporated in vacuo _two inputs. The product thus obtained is a yellow oil which crystallizes immediately.

Yield: 0.6 g (91%) of the title compound.

97-98 'C (2-propanol)

Analysis calculated for C ₁₁ H ₁₀ N ₂ O (186.2): C, 70.95; H, 5.41; N, 15.04; ² Found% C, 71.24; H, 5.93; N, 15.34.

IR (KBr): 2920; 2270; 1750 cm ^-1 .

The starting material of Example 2 was prepared as follows:

a) 151 g (0.52 mol) of diethyl (1-phenyl-4-oxo-2,2-azetidine- ³ -dicarboxylate) (JC Sheehan, AK Bose: J. Am. Chem. Soc. 72 , 5158, [1950}), 150 ml of dimethyl sulfoxide 36,5 g of NaCl and 18.7 ml (1.04 mole) water are stirred for 4-5 hours at 170-180 ° C in an oil bath. The reaction mixture was poured into 1350 ml of water ³ The reaction mixture was extracted with ether (3 x 200 mL), the layers were separated, the aqueous layer was saturated with sodium chloride and extracted with ether (3 x 100 mL), the combined ether solution was dried over magnesium sulfate, filtered and the filtrate was evaporated.

Yield: 106.5 g (94%) of ethyl (1-phenyl-4-oxo-2-azetidine carboxylate).

Mp: 34-36 ° C.

IR (KBr): 2900; 1750-1720 cm ^-1 . ⁴¹

1 H-NMR (CDCl 3):

δ 1.25 t (3H); 3.25 m (2H); 4.25 q (2H);

4.5 m (1H), 7.3 s (5H).

b) To a solution of 106.5 g (0.486 mol) of ethyl (1-phenyl-4-oxo-2-azetidinecarboxylate) prepared in Example 2a) in 700 ml of ⁵ * methanol was added 18.74 g (0.493 mol) of sodium [tetrahydro- borate (in)] is added while cooling with external ice water and stirring. Dilute the mixture was acidified with hydrochloric acid and then neutralized with disodium phosphate, the methanol is distilled off under vacuum - ** ⁵ Juk.

Yield: 65 g (76%) of 1-phenyl-4- (hydroxymethyl) -2-azetidinone.

M.p. 100-102 C (ethyl acetate petroleum ether)

Analysis for C ₁₀ H "NO ₂ (177.20) ⁶⁰ összegképlet- from:

Found: C, 67.78; H, 6.26; N, 7.91; found %; C, 67.52; H, 6.19; N, 8.20.

c) To a solution of 15 g (0.085 mole) of 1-phenyl-4- (hydroxymethyl) -2-azetidinone prepared in Example 2b in 40 ml of pyridine 65 was added 7.7 ml (11, Mesyl chloride (7 g, 0.10 mol) was added dropwise. After stirring for 1 hour, water (100 mL) was added slowly. The precipitated crystalline material is filtered off.

Yield: 18.8 g (87%) of i-phenyl-4- (mesyloxymethyl) -2-azetidinone.

86-87 ° C (ethanol).

Elemental analysis for the formula Ci, H ₁₃ NO ₄ S (255.28):

calculated%:

C, 51.75; H, 5.13; N, 5.49; S, 12.56; found %:

C, 52.18; H, 5.10; N, 5.38. S, 12.41.

IR (KBr): 2950; 1740 cm ^-1 .

1 H-NMR (CDCl 3):

δ 2.9 s (3H); 3.1-3.3 m (2H); 6.3-6.6 m (3H);

7.2-7.5 m (5H).

d) 18.8 g (0.074 mol) of 1-phenyl-4- (mesyloxymethyl) -2-azetidinone prepared in Example 2c in 80 ml of anhydrous acetone with 18.8 g (0.125 mol) of sodium iodide for 4 hours. while stirring. Water (100 mL) was added to the reaction mixture, and the precipitated crystal was filtered off and recrystallized from ethanol.

Yield: 18.1 g (89%) of 1-phenyl-4- (iodomethyl) -2-azetidinone.

Elemental analysis for C ₁₀ H ₁₀ INO (287.10):

calculated%:

C, 41.83%; H, 3.51; N, 4.88; I, 44.20; found %:

C, 41.61; H, 3.85; N, 5.07; I 44.77.

IR (KBr); 1735 cm ^-1 .

1 H-NMR (CDCl 3):

δ 2.80 dd (1H); 3.27 dd (1H); 3.35 dd (1H); 3.72 dd (1H); 4.14 m (1H); 7.30 m (5H). ¹³ C-NMR (CDCl 3):

δ 6.08; 44.41; 51.15; 116.74; 124.08; 124.24; 129.32; 162.90.

e) To a solution of 1-phenyl-4- (hydroxymethyl) -2-azetidinone (22.5 g, 0.127 mol) prepared in Example 2b in 50 ml of anhydrous pyridine was added dropwise 15 ml of mesyl chloride under reflux for half an hour. After boiling and pouring into water (400 mL), the precipitated crystalline material is filtered off, washed with water and recrystallized from ethanol.

Yield: 13.2 g (53%) of 1-phenyl-4- (chloromethyl) -2-azetidinone.

97-98 'C (ethanol)

Elemental analysis for C, ₀ H ₁₀ ClNO (195.65):

calculated%:

C, 61.39; H, 5.15; Cl, 18.12; N, 7.16; found %:

C, 61.13; H, 5.26; Cl, 18.17; N, 7.20.

From the product of Examples 2d and 2e, the title compound of Example 2 can be prepared.

Claims (1)

A patent claim Process for the preparation of new compounds of formula VI in this formula R ^{1 is} optionally substituted by one or more methoxy 187,175 is substituted phenyl or benzyl, characterized in that a compound of formula V wherein R 'is as defined above and M is halogen, reacted with an alkali metal cyanide.