NO771106L - PROCEDURE FOR PREPARING ETHER - Google Patents

Description

The invention relates to a method for the production of ethers.

Norwegian patent application no. 76.3473 discloses, among other things, ethers of clavulanic acid of formula (I):

where R^ is a group such that CO 2 R^ is an ester group, and R 2 is an inert organic group with up to 18 carbon atoms.

The invention provides a process for the preparation of a compound of formula (II):

where R^ is defined as in formula (I), is a hydrogen atom or an alkyl group with 1-4 carbon atoms, R4 is a hydrogen atom or an alkyl group with 1-4 carbon atoms, and R-- is a group such that CR^R^ The Rg part is an inert organic group with up to 18 carbon atoms. The method comprises reaction of ^jgn^ compound of formula

(III):

where R^ is as defined with respect to formula (II), with a compound of formula (IV):

wherein X is I, Br or Cl or equivalent, and R 3 , R 4 and R 5 are as defined with respect to formula (II), in the presence of a source of silver ions.

The reaction is most suitably carried out in the presence of calcium oxide, e.g. 1-2 equivalents of powdered calcium oxide per equivalent of the compound of formula (III).

The preferred source of silver ions is sulfur dioxide. In general, approx. 1-2 equivalents per equivalent of the compound of formula (III).

Suitable values for R^ include the hydrogen atom and methyl-,

the ethyl, n-propyl and n-butyl groups.

Suitable values for R 4 include the hydrogen atom and the methyl, ethyl, n-propyl and n-butyl groups.

A preferred value for R^ is the hydrogen atom, and a preferred value for R4 is the hydrogen atom so that it will be understood that certain preferred methods according to the invention are adapted for providing compounds of formula (II) where the CR3R4R5 portion is a CH2-R< 1->group where CH2R<*>is an inert organic group with up to 18 carbon atoms.

Suitable values for Rj. includes the hydrogen atom and methyl, ethyl, n-propyl, n-butyl, n-pentyl, iso-propyl, vinyl, phenyl, benzyl, p-methoxybenzyl and similar groups.

Especially suitable values for. R 1 includes the hydrogen atom and the methyl, ethyl, benzyl and vinyl groups.

Favorable values for R,_ include the hydrogen atom and. the methyl and ethyl groups.

One preferred value for Rg is the hydrogen atom.

A further preferred value for R^ is the methyl group.

Strongly favored methods according to the invention are those which are adapted for the preparation of the compounds of formal (II) where CR 3 R 4 R 5 is a methyl or ethyl group. The Bstérgroup C^R^ chosen can be any

suitable group which is described in Norwegian patent applications no. 76.3473 and 75.1407.

Preferably, the ester group is one which is readily converted to a salt corresponding to the compound of formula (II) by mild hydrolysis or hydrogenolysis as described in the above patent applications.

Particularly suitable esters include the benzyl, p-methoxybenzyl, methyl and methoxymethyl esters.

The etherification reaction is generally carried out in an inert environment at non-extreme temperatures.

Suitable solvents for the reaction include hydrocarbon solvents, e.g. benzene, toluene and the like, and other conventional solvents, e.g.; ethyl acetate, tetrahydrofuran, acetone and the like.

The reaction can best be carried out at a temperature of from

about. 10 to approx. 100°C, e.g. at 30-80°C.

It is desirable that the reaction mixture is kept under

anhydrous conditions, e.g. by application of. calcium oxide.

Then: as soon as the reaction is over (e.g. determined by TLC), the mixture is allowed to cool, filtered to remove suspended

solids and then evaporated. If desired, the resulting material can be purified by such conventional methods as column chromatography.

Particularly suitable esters of clavulanic acid for use in connection with the invention include those having the formulas (V) and

(WE):

where A is an alkyl group with 1-8 carbon atoms which is optionally substituted with halogen or a group of the formula OA<4>, OCOA 4,

4 4 4

SA , SO«A where A is a hydrocarbon group with up to txl 6 carbon atoms; A 2 is a hydrogen atom, an alkyl group with up to 4 carbon atoms or a phenyl group optionally substituted with halo-5 5 5

gene or with a group A or OA where A is an alkyl group 5

' ■'" • ' 3'' ■

with up to 6 carbon atoms; and A is a phenyl group which optionally

5 5

is substituted by halogen or by a group A or OA where

5

A is an alkyl group.

In one further aspect, the invention comprises a process for the preparation of a compound of formula (VII):

or a salt thereof, where R^, and Rj. is as defined with respect to formula (II), and the process comprises hydrogenation of a hydrogenolyzable ester of the compound of formula (VII) or hydrolysis of one hydrolyzable ester of the compound of formula (VII).

The hydrolysis and hydrogenolysis can be carried out as described

in the Norwegian patent applications no. 76.3473 and 75.1407.

A particularly suitable hydrolyzable ester is the methoxymethyl ester. Hydrolysis can be carried out using LiOH, NaOH, KOH or equivalent agents.

Particularly suitable hydrogenolyzable esters include the benzyl and methoxybenzyl esters. Hydrogenation can be carried out at atmospheric pressure of hydrogen in the presence of a transition metal catalyst, e.g. palladium, e.g. on a carrier, e.g. charcoal.

Most conveniently, the deesterification is carried out in the presence of a lithium, sodium, potassium, calcium or other base; for example, the hydrogenation can take place in the presence of an alkali or alkaline earth metal carbonate or bicarbonate, e.g. LijCO^c^NacO^^?NaHCO^i K2C03^' KHCOgO CaCO^^or the like. If no base is involved in the deesterification, then the free acid results, and this can then be neutralized if desired.

The salts thus formed can be esterified if desired, e.g. by the methods described in the Norwegian applications no. 76.3473 and 75.14o7.

From the foregoing, it will be understood that in a complex aspect the invention provides a method for the preparation of a compound of formula (VII) as defined above or a salt or ester thereof, and the method comprises reaction of a compound of formula (III) which defined above, with a compound of formula (IV) as defined above, in the presence of a source of silver ions, and then, if desired, converting the thus formed ester of formula (II) as defined above, into a compound of formula (VII) as defined above, or a salt thereof, and then, if desired, esterification of the compound of formula (VII) or a salt thereof. The compounds according to the invention can be useful in pharmaceutical preparations essentially as described in the Norwegian applications no. 76.3473 and 75.1407.

The invention provides a method for the preparation of sodium, potassium, calcium and magnesium salts of the compounds of formula (VII), and the method comprises bringing a solution of the lithium salt of a compound of formula (VII) in

e

contact with cation exchange resins x form of the sodium, calxura-j calcium or magnesium salt, and then elution of the desired salt from the resin.

Normally, the elution solvent is water or water mixed with organic solvents such as methanol, ethanol, acetone or the like. The elution solvent is preferably water. The cation exchange resin is preferably present in large excess, e.g. at least in eight times profit and more suitable at least ten times profit.

In the simplest form of the method, the solution of the lithium salt is simply percolated through a layer of the resin.

The desired salt can be obtained from solution by conventional methods such as freeze-drying, evaporation, precipitation using an organic solvent or the like. If desired, the salt can be recrystallized to further improve purity. Suitable cation exchange resins include cross-linked polystyrene/divinylbenzene copolymers substituted with sulfonic acid moieties, e.g. "Amberlite" IR-120, IR-118 or IR-122, "Dowex** .50X8, "Zerålit" 225, "Bio Rad" AG 50W-X8, "Ionac" C250, C255 or 258.

The following examples illustrate the invention:

Example 1

p-Methoxybenzyl-O-ethylclavulanate

A mixture of 3.19 g of p-ethoxybenzyl clavulanate, 4.0 g of powdered calcium oxide, 4.0 g of silver oxide and 6 ml of ethyl iodide in 50 ml of benzene was refluxed for 2 hours. The cooled reaction mixture was filtered and the filtrate evaporated to give a

oil which was chromatographed over silica gel (30g).Eluent-

ing the column with ethyl acetate/cyclohexane (1:4) gave the title compound (0.74 g) in pure form identical to an authentic sample (comparisons by IR and <T>J N.M.R.).

A similar result can be obtained by replacing the ethyl iodide with ethyl bromide and by carrying out the reaction at 40°C for a longer period of time.

The corresponding methyl ether can also be prepared by replacing methyl iodide with the above-mentioned ethyl iodide.

Example 2

p-Methoxybenzyl-O-benzylclavulanate

A mixture of 3.19 g of p-methoxybenzylclavulanate, 4.0 g of powdered calcium oxide, 4.0 g of silver oxide and 5 ml of benzyl bromide in 50 ml of benzene was refluxed for 2 hours. The cooled reaction mixture was filtered and the filtrate evaporated so that an oil was obtained which was chromatographed over. silica gel (36 g). Elution of the column with ethyl acetate/cyclohexane (1:4) gave the title compound (1»0 gj^g (liquid filra) 1810, 1750, 1700, 1310, 1250, 1180 and 1040 cm"<1>, <<£>(CDClg) 7.22 (5H, s, ArH ), 7.19 (2H, d, J = - 9Hz, ArH),, 6.76 (2H, d, J = 9Hz«ArH) , 5.58 (1H, d , J = 2.5Hz, 5-CH), 5.08 (2H, s, -CH2Ar), 5.00 (1H, broad s, 3-CH), 4.80 (1H, broad t, J = 8Hz , 8-CH), 4.38 (2H, s, -CH2ArK 4.05 (2H, broad d, .. J « 8Hz, 9-CH2), 3.70 (3H, s, OCH3), 3.40 (1H, dd, £= 17Hz, J' x 2.5Hz, 6<*-CH), and 2.96 (1H, d, J = 17Hz, 6/3-CH)..

Example 3

p-Methoxybenzyl-O^ allyl clavulanate

A mixture of 3.19 g of p-methoxybenzylclavulanate, 4.0 g of powdered calcium oxide, 4.0 g of silver oxide and 4 ml of allyl bromide in 30 ml of benzene was stirred at room temperature for 66 hours. The mixture was filtered and the filtrate evaporated to give an oil which

was chromatographed over 20 g of silica gel*Elution of the column with cyclohexane/ethyl acetate (4:1) gave the title compound

(0.65 g), Ymax (liquid film) 3020, 1810, 1750, 1700, 1310, 1255, 1080 and lo40 cm"1, 6 (CDCl3) 7.30 (2H, d, J * 9Hz,ArH), 6 .86 (2H,

d, J = 9 Hz, ArH), 5.95 (1H, m, C=CH), 5.67 (1H, d, J 2.5Hz, . 5-CH), 5.32 (2H, m, C=CH), 5.13 (2H, s., -CHjAr), 5.06 (1H, s, 3-CH), 4.83 (1H, broad t, J = 8HZ, 8-CH), 4 .06 (2H, broad d, J 8Hz, 9-CH2), 3.92 (2H, m, -OCH2-CH=CH2), 3.80 (3H, s, 0CH_3), 3.50 (lH,

dd, J = 17 Hz, J' = 2.5 Hz, 6of-CH), and 3»00 (1H, d, .J == 17 Hz, 6/3-CH) .

Example 4

Benzyl-O-methylclavulanate

A mixture of 8/67 g of benzylclavulanate, 12 g of calcium oxide, 12 g of silver oxide and 15 ml of methyl iodide in 50 ml of benzene was heated under reflux for 2 hours. The mixture was allowed to cool, filtered and the filtrate evaporated to give an oil

which was chromatographed over silica gel (50 g). Elution with ethyl acetate/cyclohexane-1(-|4) gave the title compound (2.81 g).

Example 5

Benzyl-O-nonyl clavulanate

2.89 g of benzylclavulanate in 10 ml of ethyl acetate and 12.7 g of iodononane were heated under reflux with stirring in the presence of 4 g of silver oxide and 4 g of calcium oxide for 3 hours. TLC showed a fast-running zone and a highly reduced zone due to starting material. The mixture was filtered, the insoluble washed with 50 ml of ethyl acetate and the filtrate evaporated under reduced pressure to a dark oil. This was subjected to column chromatography on silica gel, using ethyl acetate and cyclohexane varying from 10 to 1:2 as elution media. Fractions after the nonyl iodide was eluted contained the product, which was isolated as a pale yellow oil by evaporation of the solvents.

Yield: 0.64 g. IR. (l/f): 1805, 1750, 1695 cm<**1>.

N.M.R. (CDCl3)£: 0.86 (3H, t, J 7Hz, CH3), 1.25 (14H, m* 0-CH2-(C<H>2)7CH3), 2.98 (1H, d, J 17Hz, 6-/3-CH) , 3.31 (2H,t, J 7Hz, OCH2)7), 3.43 (1H, dd, J 17Hz and 3Hz, 6-o-CH), 3.98 ( 2H, d, J 7Hz, CH2CH=), 4>78{ IB, t, J 7Hz,CH=), 5.02 (1H, S, 3-CH), 5.12 (2H, s,PhCH2), 5.61 (1H, d, J 3Hz, 5-CH) and 7.27 (5H, s, CgHg).

Example 6

DL- benzyl- Q- 2- butylclavulanate

2.89 g of benzylclavulanate in 7 ml of ethyl acetate and 9 g of 2-iodo-butane were refluxed with stirring in the presence of 4 g of silver oxide and 4 g of calcium oxide for 2 1/2 hours. The insoluble materials were filtered off and the filtrate concentrated in vacuo to a yellow oil, which was subjected to column chromatography on silica gel using ethyl acetate and cyclohexane varying from 1:10 to 1:2 in ratio. The ether was eluted after the 2-iodobutane. Fractions containing the ether (by TLC) were evaporated in vacuo to give the compound (0.57 g) as a pale yellow oil. I.R. (l/f) 1808, 1753, 1698 cm""<1>.

NMR (CDCl 3 ) So, 84 (3H, t*J 7HZ, CH 2 CH 3 ), 1.07 (3H, d, J 7 Hz, CH-CH 3 ), 1.26 - 1.63 (2H, m, CH 2 CH 3 ), 2 .96 (lH, d, J 17Hz, 6-/3-CH) , 3.26 (1H, qt, J, 7Hz OCH), 3.41 (OH, dd, J 17Hz, 3Hz, 6-a-CH ), 3.8 - 4.25 (1H, m, 9-CH2), 4.77 (1H, t, J 8Hz 8-CH), 5.20 (1H, s, 3-CH), 5.12 (2H, S, CH2Ph), 5.90 (lH, d, J 3Hz, 5-CH) 7.28 (5H, S,

Example 7

Benzyl- T- Q- £- amyl clavulanate

2.89 g of benzylclavulanate in 20 ml of ethyl acetate and 2-iodo-2-methylbutane (6.5 ml, 9.9 g) were stirred at room temperature in the presence of 4 g of silver oxide and 4 g of calcium oxide for 3 hours. The insoluble material was filtered off, washed with .50 ml of ethyl acetate and the filtrate evaporated under reduced pressure to a dark oil, which was subjected to column chromatography on silica gel, eluting with cyclohexane/ethyl acetate varying from 100 ml to 3:1, to give 0.43 g of the title product as a pale yellow oil.

I.R. 1805, 1755, 1698 cm , (liquid frlm).

N.M.R. (CDCl3)é0.83 (3H, t, J 7Hz, CH2CH3), 1.11 (6H, S, (CH3)2), 1.46 (2H, q, J 7Hz,<C>H2CH3), 2, 96 (lH, d, J 17Hz, 6-0-CH), 3.40 (lH, dd* J 17 and 3Hz, 6-a-CH), 3.6 - 4.3 (2H, m, =CHCH2 ), 4.74 (1H, dt, J 7 and~f2Hz, CH=), 5.0 (1H, d, J~2Hz, 3-CH), 5.12 (2H, s, PhCH2), 5, 59 (1H, d, J 3Hz, 5-CH), 7.27 (5H, s, CgHg)..

Example 8

Lithium-O-ethyl clay cyanate

2.5 g of p-methoxybenzyl-O-ethylclavulanate in 25 ml of tetrahydrofuran containing 0.1 ml of water was hydrogenated over 10% palladium charcoal (0.8 g). After 2 hours, the absence of starting material was shown by TLC. The catalyst was removed

by filtration through a layer of finely divided silica, the filtrate was diluted with equal parts by volume of water and titrated to pH 7.0 with 1 M lithium hydroxide solution. Evaporation of the solvents and trituration with acetone gave the lithium salt in the form of a

faint cream crystalline solid (1.05 g).

(The sodium salt was prepared in an identical manner using 1 m NaOH solution" yield 0.85 g). Properties of the lithium salt: I.R. (nujol mull) 1785 {/3-lactamC=0) 1685 (C=C)

1615 em"<*1>(-C02-). (The lithium and sodium salts of the methyl ether can be prepared in an identical manner).

Example 9

Preparation of crystalline lithium-clavulanyl-O-methyl ether

r; Amorphous lithium clavulanate methyl ether prepared as described above was dissolved in approx. 1 ml of water. To this solution at ambient temperature was added approx. 30 ml of acetonitrile. The mixture was cooled in an ice bath and scraped until crystallization began

(approx. 30 min.). The colorless microcrystals were filtered off and dried so that 0.13 g of the desired crystalline product was obtained. Analysis indicated a highly pure product.

Example 10

Preparation of crystalline sodium clavulanic methyl ether

(a) 500 mg of amorphous sodium clavulanic methyl ether was added to 50 ml

ethyl acetate and the mixture gently boiled for 5 minutes. The solution was filtered hot and the filtrate was allowed to cool to room temperature whereupon crystals appeared. When the crystallization was found to be complete, the crystals were filtered off and dried in dry air to give the desired crystalline sodium clavulanic acid methyl ether. (b) 100 mg of amorphous sodium clavulanic methyl ether was dissolved in 4 ml of hot acetone. The solution was filtered and the filtrate was allowed to cool to room temperature. To this was added ether (approx. 20 ml) dropwise until crystals appeared. The suspension was boiled to dissolve the crystals and then allowed to cool. After cooling in an ice bath and scraping for a few minutes, the desired crystalline materials formed and were collected by filtration to give fine crystals.

Example 11

Methoxymethyl-O-ethylclavulanate

Methoxymethylclavulanate (2.43 g, 0.01 mol), anhydrous sodium carbonate (4 g, large excess) and triethyloxonium tetrafluoroborate (5.7 g, 0.03 mol) in 125 ml of dry dichloromethane at -30°C

'was stirred vigorously. The mixture was allowed to warm to room temperature

for 1 hour and was stirred for 4 hours. The reaction was followed by TLC. 20 ml of water was added, agitated and separated. The solvent layer was dried over sodium sulfate, filtered and evaporated to a pale yellow oil. This was subjected to column chromatography over silica gel, eluted with ethyl acetate/methylcyclopentane (1:3) then with ethyl acetate and cyclohexane which varied from 2:1 to pure ethyl acetate. The first eluted product was the title compound (1.5 g) followed by a small amount of unreacted starting material (0.1 g).

I.R. (film) 1805 (p-lactam c=0) 1755 (ester C=0) 1700 (C=C) N.M.R. (CDCl3) 1.18 (3H, t, J 7Hz, <CFL>jCHg) 3.02 (1H, d, J 17Hz, 6-/3-CH) 3.42 (2H, q, J 7Hz, CH3CH. 2) 3.44 (lH, dd, J 17 and 3 Hz, 6-a-CH) 3.45 (3H, S, 0CH3J( 4.04 (2H, d, J 7Hz, CH_2-CH=)

4.86 (1H, bt, J 7Hz, CH2-CH=) 5.04 (1H, bs. 3-CH) 5.23, 5.30 (2H, ABq, J 5HZ, 0CH2O) 5.65( f(1H, d, J 3Hz, 5-CH).

The corresponding methyl ether can be prepared in an exactly analogous manner.

Example 12

Lithium H3- ethyl clavulanate

0.5 g of methoxymethyl-O-ethylclavulanate in 5 ml of tetrahydrofuran was added to 25 ml of water. The mixture was maintained at pH 8.5-9.0 by the addition of 1.0 ml of lithium hydroxide solution using a "Metrohm" pH-Stat (1.8 ml required). The aqueous solution was evaporated to dryness in vacuo and triturated with acetone to give a pale yellow crystalline solid, which was collected, washed with ether and air-dried to give 0.25 g of the title compound. It had the following properties: 1. R. (Nujol mull) 1785 (/3-lactam C=0) 1685 (C=C) 1615 cm"<1>(-C0~) N.M.R. (in D20) 1.11 (3H , t, J 7Hz, CH_2CH3) 3.05 (lH, d, J 17Hz, 6-/9-CH) 3.48 (2H, q, J 7Hz, CH2CH3) 3.50 (lH, dd, J 17HZ, and 3Hz, 6-α-CH) 4.04 (2H,d, J 7Hz, CH2«CH=) 4.82 (lH, t, J 7Hz, CH=) 4.88 (lH, £ 3-CH) 5.654 (1H, d, J 3Hz, 5-CH).

The lithium salt of the corresponding methyl ether can be prepared in an exactly analogous manner.

Example 13.",

Conversion of lithium O- et<y>lclavulanate to sodium O- ethylclavulanate by ion exchange

0.25 g of lithium O-ethylclavulanate in 2 ml of water was passed through a bed of "Amberlite" lR120 (standard grade)

(Na + form) (8 ml wet resin). The eluate was collected and evaporated to dryness in vacuo. The residue was treated with acetone/ether, filtered off, washed with ether and air-dried, so that 0/17 g of sodium O-ethylclavulanate was obtained, identical to that produced by hydrogenolysis of p-methoxybenzyl-o-ethylclavulanate (q.v.)

The sodium salt of the corresponding methyl ether can also be prepared in this way.

Claims (13)

1. Process © for the preparation of a compound of formula (VII): C02H or a salt or ester thereof, where R^ is a hydrogen atom or an alkyl group with 1-4 carbon atoms, R^ is a hydrogen atom or an alkyl group with 1-4 carbon atoms, and R^ is a group such that CR^ R^ Rjj - part is an inert organic group with up to 18 carbon atoms, characterized by turnover of a compound of formula (lii): H —P \_ l CH20H J—-nn/" (HD 0 C02 R1 where is a group such that C02R^ is an ester group with a compound of formula (IV): where X. is I, Br or Cl or higher equivalent, and R3# R4 and R,, is as defined for formula (II), in the presence of a source of silver ions? and then, if desired, conversion of the thus formed ester into the free carboxylic acid or a salt thereof and then, if desired, conversion of the thus formed acid or a salt thereof into an ester. 2. Process for producing a compound of formula (II): where COjRjL is an ester group, R3 is a hydrogen atom or an alkyl group with 1-4 carbon atoms, R^ is a hydrogen atom or an alkyl group with 1-4 carbon atoms, and R& is such a group that CR3 <R> 4 <R5> ~ the proportion is one inert organic group with up to 18 carbon atoms, characterized by reaction of a compound of formula (III): where R^ is as defined with respect to formula (II), with a compound of formula (IV): where X is I, Br or Cl or some equivalent, and R₂, R₂ and R₂ is as defined with respect to formula (II), in the presence of a source of silver ions. 3. Process as stated in claim 1 or 2, characterized in that R^ is a hydrogen atom, R^ is a hydrogen atom and R5 is a hydrogen atom or methyl, ethyl, n-propyl, n-butyl, n-pentyl, iso-pentyl, iso-propyl, vinyl, phenyl, benzyl or p-methoxybenzyl group . 4. Method as set forth in claim 1 or 2, characterized in that R^ is a hydrogen atom, R^ is a hydrogen atom and R^ is a hydrogen atom or a methyl group. 5. Method as stated in any of claims 1-4, characterized in that the reaction mixture contains calcium oxide. 6. Method as stated in any one of claims 1-5, characterized in that the source of silver ions is silver oxide. 7. Process for producing a compound of formula (VII) as defined in claim 1, or a salt thereof, characterized by deesterification of an ester of the for-^ bond of formula (VII). 8 . Procedure, as stated in claim 7, characterized in that it comprises mild base hydrolysis. 9. Procedure as stated in claim 8, characterized in that it comprises hydrolysis of the methoxymethyl ester. 10. Procedure as stated in claim 7, characterized in that it comprises hydrogenation of a benzyl or p-methoxybehzyl ester. 11. Procedure as stated in claim 10, characterized in that it is carried out in the presence of an alkali or alkaline earth metal carbonate or bicarbonate. 12. Process for producing a sodium, potassium, or calcium salt of a compound of formula (VII) as defined in claim 1, characterized in that it comprises bringing the corresponding lithium salt into contact with a cation exchange resin in the form of its sodium ,, potassium or calcium salt and then elution of the desired salt from the resin. 13. Procedure as specified in claim 12, can be distinguished by the fact that the source of ions is a cross-linked polystyrene/divinylbenzene copolymer which is substituted with sulphonic acid parts in its sodium, potassium or calcium forms.