GB2291874A

GB2291874A - Etherification process

Info

Publication number: GB2291874A
Application number: GB9513828A
Authority: GB
Inventors: Martin Charles Bowden; Stephen Martin Brown; Raymond Vincent Heavon Jones; Michael Charles Henry Standen; Christopher John Urch
Original assignee: Zeneca Ltd
Current assignee: Syngenta Ltd
Priority date: 1994-07-28
Filing date: 1995-07-06
Publication date: 1996-02-07
Anticipated expiration: 2015-07-06
Also published as: GB2291874B; FR2723090A1; GB9415291D0; DE19525393A1; DE19525393B4; GB9513828D0; FR2723090B1

Description

CHEMICAL PROCESS 2291874 The present invention provides a process for the

preparation of methyl 3, 3-dimethoxy-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]propanoate or (.E) methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate which are useful intermediates in the agrochemical industry.

The present invention provides a process for the preparation of a compound of formula (1), wherein W is CH 302 CCHCH(OCH 3)21 the process comprising reacting a compound of formula (II), wherein W is CH 3 0 2 CCHCH(OCH 3)21 with 4,6-dichloropyrimidine in the presence of a suitable base in an environment which is substantially free of methanol.

In one aspect the present invention provides a process for the preparation of the compound (I) the process comprising the steps:

(a) protonating a compound of formula (III) to form a compound of formula (II); and (b) reacting a compound of formula (II) with 4,6-dichloropyrimidine in the presence of a suitable base in an environment which is substantially free of methanol, wherein W is CH 302 CCHCH(OCH 3)2 or CH 302 CCCH.OCH 3, and M is a metal or other suitable counterion.

In another aspect the present invention provides a process for the preparation of the compound (1) the process comprising reacting a compound of formula (III) with 4,6-dichloropyrimidine in an environment which is substantially free of methanol, wherein W is CH 302 CCHCH(OCH 3)2 and M is a metal or other suitable counteri on.

In another aspect the present invention provides a process for the preparation of a compound of formula (I), wherein W is CH 3 0 2 CCHCH(OCH 3)2 or CH 3 0 2 CCCH.OCH 31 the process comprising the steps:

(a') reacting a compound of formula (IV) with methanol in the presence of a base to form a compound of formula (II), a compound of formula (III) or a mixture of compounds of formulae (II) and (III); and either M or 0) 0 i) reacting said mixture with 4,6-dichloropyrimidine in an environment which is substantially free of methanol and optionally in the presence of a suitable base; protonating the compound of formula (III) in said mixture to form compound of formula (II); and reacting the compound of formula (II) with 4,6-dichloropyrimidine in the presence of a suitable base and in an environment which is substantially free of methanol; wherein W is CH 302 CCHCH(OCH 3)2 or CH 302 CCCH.OCH 3, and M is a metal or other suitable counterion. The relative amounts of the compounds of formulae (II) and (III) formed depend on both the pKa of, and the amount of, base used in step (a').

It is preferred that the base used in step (a') is present in the range 0. 001 to 0.9, particularly 0.001 to 0.75 (especially 0.005 to 0.2) equivalents. The base used in step (a') can be a methoxide (such as an alkali metal or alkaline earth metal methoxide of formula Ax(OCH 3)y# wherein A is alkali metal or alkaline earth metal, and x and y fulfill valency requirements, for example sodium methoxide, potassium methoxide or magnesium methoxide), an alkali metal carbonate or bicarbonate (such as potassium carbonate or potassium bicarbonate), an amine of formula R'VR"N (wherein R', C and R" are, independently, C 1-6 alky]; such as triethylamine or fi,fi-diisopropylethylamine), a 5 or 6-membered nitrogen containing ring (such as imidazole, pyrazole, pyrrole, 1,2,3-triazole, 1, 2,4-triazole or pyridine) optionally substituted by C,, alkyl or NR 1 R 2 (wherein R' and R2 are, independentl Y C 1-6 alkyl) such as N(CH 3)2, an ammonium salt of formula (R 3R 4 R5R 6 N +) M X- p (wherein R 3, R 4 ' R5 are, independently, C 1-6 alkyl or benzy]; X is a suitable anion, such as hydroxide or C 1-6 alkoxide (preferably methoxide); and m and p fulfill valency requirements) such as (C6 H 5 CH 2) (CH 3)3 CHO a nitrogen containing polycyclic ring system (for example hexamethylenetetramine or 1,4-diazabicyclo[2,2,2]octane), or a basic ion exchange resin (such as Amberlyst A21, DOWEX 1, or Amberlyst A27 in methoxide form).

When M is a metal it is preferably an alkali or alkaline earth metal and is, for example, sodium, potassium or magnesium. When M is a counterion it is, for example, (C 1-6 alkyl)4 N+ (such as tetra-1]- -butylammonium cation).

Alkyl contains from 1 to 6, preferably from 1 to 4, carbon atoms and is straight or branched chain. It is, for example, methyl, ethyl, ji-propyl, iso-propyl or n-butyl.

The foregoing processes of the invention are shown diagrammatically in Scheme I. Throughout Scheme I W and M are as defined above.

A compound of formula (III) can be formed by reacting a compound of formula (IV) with methanol in the presence of a base (such as sodium or magnesium methoxide, potassium carbonate or triethylamine), in a suitable solvent (such as methanol, an aromatic, aliphatic or alicyclic hydrocarbon (for example toluene, a xylene, benzene or cyclohexane), a chlorinated solvent such as a halobenzene (for example chlorobenzene) or a haloalkane (for example dichloromethane), an ether (such as tetrahydrofuran, diethyl ether, tert-butylmethyl ether or a capped glyme), or an ester (preferably a methyl ester, such as methyl acetate or methyl formate), _R,N-dimethylformamide or 11-methylpyrrolidinone). When methanol is used as solvent it is preferred that the reaction is carried out in the temperature range -50-20C (preferably -20-100C). When a solvent other than methanol is used (methanol being present as a reactant or co-solvent) it is preferred that the reaction is carried out in the temperature range -50-50C (such as ambient temperature).

A compound of formula (III) which is substantially free of methanol can be obtained by removing methanol, for example by evaporation, distillation (preferably distillation under reduced pressure and at a temperature below 10C), azeotropically or by use of a membrane.

A compound of formula (II) can be prepared by protonating a compound of formula (III) using an acid (such as an organic acid (for example acetic acid) or a mineral acid (for example hydrochloric acid)). A compound of formula (II) which is substantially free of methanol can be obtained by removing methanol by distillation.

Alternatively, a compound of formula (II) or (III) or a mixture thereof can be prepared by reacting a compound of formula (IV) with methanol in the presence of a base (such as sodium methoxide, magnesium methoxide, potassium bicarbonate, potassium carbonate, triethylamine or diisopropylethylamine). In general an ionic base will lead to a compound of formula (III), and, when less than one equivalent of an ionic base is used a mixture of compounds of formulae (II) and (III) is produced.

A compound of formula (I) can be prepared by reacting 4,6dichloropyrimidine with a compound of formula (11) in the presence of a suitable base (such as an alkali metal carbonate, for example potassium carbonate) and optionally in a suitable solvent (such as ja,li-dimethyl f ormami de).

Alternatively, a compound of formula (I) can be produced by reacting 4,6dichloropyrimidine with a compound of formula (III) in a suitable solvent (such as ff,li-dimethylformamide).

EXAMPLE 1

This Example illustrates the preparation of methyl 3,3-dimethoxy-2-[2hydroxyphenyl]propanoate.

3-(m-Methoxy)methylenebenzofuran-2(3H)-one (11g) was slurried in methanol (100cm3) and the slurry was cooled to below 10% under a nitrogen blanket. Sodium methoxide (30% solution in methanol, 15.7g) was added over 15 minutes keeping the temperature below 100C. The reaction mixture was stirred below 10C for 1 hour.

The resulting yellow solution was added to iced water (400cm3) and acetic acid (10cm3) added over 30 minutes keeping the temperature below 200C. The methanol was removed by vacuum distillation and the title compound extracted with dichloromethane (2x2OOcm3). Then the extracts were combined and washed with water (100cm3). Distillation of the dichloromethane afforded a product, as a pale yellow oil (22.5g). Re- extraction from a dichloromethane water mixture gave a product in a crude state, as a pale yellow oil (10.6g). 1H NMR (d 6- acetone)b 3.2(s,3H); 3. 4(s,3H); 3.6(s,3H); 4.50,1H); 5.00,1H); 6.7-7.4(m,4H); 8.4(s,lH)ppm.

EXAMPLE 2

This Example illustrates the preparation of a mixture of methyl 3,3dimethoxy-2-[2-hydroxyphenyl]propanoate and its sodium salt.

3-(4x-Methoxy)methylenebenzofuran-2(3H)-one (4.4g) was slurried in methanol (40cm 3) and the slurry was cooled to below 10C. To this was added, under nitrogen, a 30% solution of sodium methoxide in methanol (0. 05cm3, 0.01eq). The reaction mixture was stirred below 10% for 1 hour after which qualitative analysis by high pressure liquid chromatography (hplc) showed the reaction to have proceeded by approximately 50%. Hplc analysis after overnight storage in a fridge showed the reaction to have proceeded 80%. [NB As the eluent for hplc was acidic the title compound which is a sodium salt converted to the other title compound on analysis].

EXAMPLE 3

This Example illustrates the preparation of methyl 3,3-dimethoxy-2-[2hydroxyphenyl]propenoate and (f.) methyl 2-[2-hydroxyphenyl]-3-methoxypropenoate.

3-(ot-Methoxy)methylenebenzofuran-2(3H)-one (1.5g) was slurried in cyclohexane (30cm 3) and stirred under nitrogen for 20 hours at room temperature. Magnesium methoxide containing some methanol (7.3g, obtained by removal of most of the methanol from an 8% solution of magnesium methoxide in methanol) was charged and the reaction mixture sonicated for 2 hours at room temperature and then stirred for 20 hours at room temperature.

To the reaction flask was charged aqueous acetic acid (50cm 3) which resulted in a slight exotherm. The product was extracted with dichloromethane (2x5Ocm3) and the extracts were washed with water (20m1). Distillation of the dichloromethane afforded the title compounds as a mixture.

EXAMPLE 4

This Example illustrates the preparation of a mixture of methyl 3,3dimethoxy-2-[2-hydroxyphenyl]propanoate and its potassium salt.

3-(a-Methoxy)methylenebenzofuran-2(3H)-one (5.5g) was slurried in methanol (50cm3) under a nitrogen blanket. The slurry was cooled to below 100C and potassium carbonate (0.70g, 0.2eq) added at such a rate to keep the temperature below 100C. The reaction mixture was stirred for 24 hours below 10C when qualitative high pressure liquid chromatography analysis (using an acidic eluent) showed approximately 80% conversion to title compounds.

EXAMPLE 5

This Example illustrates the preparation of methyl 3,3-dimethoxy-2-[2-(6chloropyrimidin-4-yloxy)phenyl]propanoate.

Methyl 3,3-dimethoxy-2-[2-hydroxyphenyl]propanoate (3.0g), t[,Ndimethylformamide (60m1), 4,6-dichloropyrimidine (4.0g) and potassium carbonate (3.0g) were heated to WC for 3 hours. The reaction mixture was then cooled to WC and filtered; and the residue was washed with _R,Ndimethylformamide (locm3). The filtrate and wash were combined and concentrated under reduced pressure at WC/10m Hg to leave the title compound (3.5g, 76%).

EXAMPLE 6

This Example illustrates the preparation of methyl 3,3-dimethoxy-2-[2-(6chloropyrimidin-4-yloxy)phenyl] propanoate.

3-(oc-Methoxy)methylenebenzofuran-2(3H)-one (5.5g) was slurried in methanol (50cml) and cooled to below 10C under an inert blanket. Sodium methoxide (30% solution in methanol, 1.249) was added keeping the temperature below 100C. The reaction mixture was stirred for 2 hours below 10C when qualitative high pressure liquid chromatography analysis showed 90% conversion to methyl 3,3-dimethoxy-2-[2-hydroxyphenyl] propanoate. [As the eluent for hplc was acidic it was methyl 3,3dimethoxy-2[-2hydroxyphenyllpropanoate, and not its sodium salt, that was detected.] After acidification of the reaction mixture and removal of the methanol by atmospheric distillation, fi,h[-dimethylformamide (50CM3) was added followed by 4,6-dichloropyrimidine (5.2g) and potassium carbonate (4.8g). The reaction mixture was stirred for 3 hours at 60% the Ja,ldimethylfonnamide removed by vacuum distillation (1OMM Hg) WC. The residue was extracted with toluene, the extracts were combined and washed with water. Analysis by comparative gas chromatography showed the title compound to be present in approximately 51% yield.

EXAMPLE 7

3-(a-Methoxy)methylenebenzofuran-2(3H)-one (4g) was slurried in methanol (40cm1) and cooled to below 10C under a nitrogen blanket. Triethylamine (0.4g, 0.2eq) was charged and the temperature held below 10C for 16 hours. The resulting yellow solution was analysed by qualitative high pressure liquid chromatography which showed the reaction to have proceeded by approximately 80%.

The methanol was removed by vacuum distillation below WC. li,t[Dimethylfomamide (10CM3), 4,6-dichloropyrimidine (2.9g) and potassium carbonate (2.7g) were added to the residue and the resulting mixture was stirred at room temperature for 20 hours. Qualitative gas chromatographic analysis showed that the reaction had proceeded by approximately 85% (conversion to title compound).

EXAMPLE 8

Methyl 3,3-dimethoxy-2-[2-hydroxyphenyl]propanoate (0.4g), 4,6dichloropyrimidine (2.8g) and potassium carbonate (3.0g) were heated at WC for 3 hours. Qualitative gas chromatographic analysis showed over 80% conversion to the title compound.

All of the Examples 9 to 21 illustrate the preparation of methyl 3,3dimethoxy-2-[2-hydroxyphenyl]propanoate or a salt thereof.

EXAMPLE 9

3-(ot-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50cm') and cooled to below 10C under a nitrogen blanket. _4,_qdiisopropylethylamine (3.22g, 1eq) was added keeping the temperature below 10C. The reaction mixture was stirred for 4 hours below 100C and then stored for 4 days below 10C after which qualitative high performance liquid chromatography (hplc) showed 80% conversion to the title compound.

EXAMPLE 10

3-((x-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50cm') and cooled to below 10% under a nitrogen blanket..U,bidiisopropylethylamine (0.32g, O.1eq) was charged keeping the temperature below 100C. The reaction mixture was stirred for 4 hours below 100C and then stored for 4 days below 10% when qualitative hplc showed approximately 80% conversion to the title compound.

EXAMPLE 11

3-(a-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50cm') and cooled to below 10% under a nitrogen blanket. Potassium bicarbonate (2.47g, 1eq) was charged keeping the temperature below 10C. The reaction mixture was stirred for 6 hours below 10% and then stored for 5 days below 100C when qualitative hplc showed 76% conversion to the title compound. [As the eluent for the hplc was acidic it was the methyl 3,3-dimethoxy-2-[2-hydroxyphenyl] propanoate, and not potassium salt, that was detected.] EXAMPLE 12

3-(ct-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50cm') and cooled to below 10C under a nitrogen blanket. 1,4DiazabicYclo[2,2,2]octane (2.83g, 1eq) was charged keeping the temperature below 100C. The reaction mixture was stirred for 5 hours below 100C when qualitative hplc showed 4% conversion to the title compound. After storage for 6 days below 10% qualitative hplc showed 77% conversion to methyl 3,3-dimethoxY-2-[2-hydroxyphenyl]propanoate.

EXAMPLE 13

3-(a-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50CM3) and cooled to below 10C under a nitrogen blanket. Imidazole (1.70g, 1eq) was charged keeping the temperature below 100C. The reaction mixture was stirred for 6 hours below 10C and then stored for 6 days below 10C when qualitative hplc showed approximately 30% conversion to methyl 3,3-dimethoxY-2-[2-hydroxyphenyl]propanoate.

EXAMPLE 14

3-((x-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50CM3) and cooled to below 10C under a nitrogen blanket. Benzy1trimethylammonium hydroxide (40% solution in methanol, 1.03g) was charged keeping the temperature below 10C. The reaction mixture was stirred for 3.5 hours below 10C when qualitative hplc showed approximately 80% conversion to methyl 3,3-dimethoxy-2-[2- hydroxyphenyl]propanoate. [As the eluent for the hplc was acidic it was the title compound, and not its salt, that was detected).

EXAMPLE 15

3-(a-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50CM3) and cooled to below 10C under a nitrogen blanket. Pyridine (0.20g) was charged keeping the temperature below 100C. The reaction mixture was stirred for 6 hours below IOOC and then stored for 5 days below 10% when qualitative hplc showed conversion (0.5%) to the title compound. After storage for 10 days below 10% pyridine (1.75g) was charged and reaction mixture stirred for 6 hours below 100C and then stored for 1 day below 10% when qualitative hplc showed conversion (0.7%) to the title compound.

EXAMPLE 16

3-(m-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50CM3) and cooled to below 10% under a nitrogen blanket. Hexamethylenetetramine (0.35g) was charged keeping the temperature below 10C. The reaction mixture was stirred for 6 hours below 10C and then stored for 4 days below 10C. As there was no visible sign of reaction extra hexamethylenetetramine (3.15g) was charged and reaction mixture stirred for 6 hours below 10C and then stored for 1 day below 10C when qualitative hplc showed conversion (1.5%) to the title compound.

EXAMPLE 17

3-(a-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50cm') and cooled to below 10C under a nitrogen blanket. 4Dimethylaminopyridine (0.30g, O.Ieq) was charged keeping the temperature below 10C. The reaction mixture was stirred for 6 hours below 10C and then stored for 3.5 days below 10C when qualitative hplc showed conversion (42%) to the title compound.

EXAMPLE 18

3-(a-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50cm') and cooled to below 10C under a nitrogen blanket. Poly(4vinylpyridine) (0.50g) was charged keeping the temperature below 10C. The reaction mixture was stirred for 6 hours below 10C and then stored for 4 days below 100C. No major discolouration to the reaction mixture had occurred thus poly(4-vinylpyridine) (2.0g) was charged and reaction mixture stirred for 6 hours below 100C and then stored for 3 days below 10C when qualitative hplc showed 0.5% conversion to the title compound.

EXAMPLE 19

3-(a-Methoxy(methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50cm') and cooled to below 10C under a nitrogen blanket. Sodium methoxide (0.027%w/v solution in methanol, 5.OCM3, 0.001eq) was charged keeping the temperature below 10C. The reaction mixture was stirred for 6 hours below 100C and then stored for 18 hours below 10C when qualitative hplc showed 2% conversion to the title compound. [As the eluent for the hplc was acidic it was the methyl 3,3-dimethoxy-2-[2hydroxyphenyl]propanoate, and not its sodium salt, that was detected].

EXAMPLE 20

Amberlyst A27 ion exchange resin (containing 45% by weight of moisture, 4. 7g) was washed with methanol (JOOCM3) and then treated with sodium methoxide (27% solution in methanol) until no chloride was detected in the effluent. The resin was then washed with methanol (50CM3) and dried under a stream of nitrogen.

3-(a,-Methoxy)methylenebenzofuran-2-(3H)-one (6.3g) was slurried in methanol (50CM3) and cooled to below 10C under a nitrogen blanket. Amberlyst A27 ion exchange resin (as prepared in the previous paragraph, 2.58g) was charged keeping the temperature below 100C. The reaction mixture was stirred for 4 hours below 10C when qualitative hplc showed 85% conversion to the title compound. [As the eluent for the hplc was acidic it was the methyl 3,3-dimethoxy-2-[2-hydroxyphenyl]propanoate, and not its salt, that was detected.

EXAMPLE 21

3-(m-Methoxy)methylenebenzofuran-2-(3H)-one (5.0g) was slurried in methanol (50CM3) and cooled to below 10C under a nitrogen blanket. Amberlyst A21 ion exchange resin (pre washed with methanol (100cml) and dried under suction, 5.0g) was charged keeping the temperature below 10'C. The reaction mixture was stirred for 6 hours and then stored for 2 days below 10C when qualitative hplc showed 5% conversion to the title compound. [As the eluent for the hplc was acidic it was the methyl 3,3dimethoxY-2-[2-hydroxyphenyl]proanoate, and not its salt, that was detected.] FORMULAE DRAWINGS (As in Description)

SCHEME1 OCH3 1 Lom 1 I on 0 0 N '::" 1 N 1 cl,,l Z 01'9 (1) -19 W 1 mo "., 9 W 1 HO"P W (111)

Claims

1. A process for the preparation of a compound of formula (I) N N 1 Cl." 1 Oll,' ? W (1) wherein W is CH 3 0 2 CCHCH(OCH 3)21 the process comprising reacting a compound of formula (If):

HO"P W wherein W is CH 302CCHCH(OCH 3)21 with 4,6-dichloropyrimidine in the presence of a suitable base in an environment which is substantially free of methanol.

2. A process for the preparation of the compound (I):

N':: 1 N 1 Cl.'-- -11 1",0""q W the process comprising the steps:

(a) protonating a compound of formula (III):

MO W to form a compound of formula (If (1) (111) 1 HO W (11) 1 with methanol in the presence of a base to form a compound of formula (I1) 1 (11) HO'P W a compound of formula (III):

MO or a mixture of compounds of formulae (II) and (III); and either 0) reacting said mixture with 4,6-dichloropyrimidine in an environment which is substantially free of methanol and optionally in the presence of a suitable base; or 0) protonating the compound of formula (III) in said mixture to form compound of formula (II); and (ii) reacting the compound of formula (II) with 4,6-dichloropyrimidine in the presence of a suitable base and in an environment which is substantially free of methanol; wherein W is CH 302CCHCH(OCH 3)2 or CH 302 CCCH.OCH 3' and M is a metal or other suitable counterion.

5. A process as claimed in claim 4 wherein the base used in step (a') is present in the range 0.001 to 0.75 equivalents.

6. A process as claimed in claim 4 wherein the base used in step (a,) is an alkali metal carbonate or bicarbonate, an amine of formula WCR"N (wherein R', W' and R" are, independently, C 1-6 alkyl), a basic ion exchange resin, a 5- or 6-membered nitrogen containing ring optionally substituted by NR1R 2 (wherein R' and R2 are, independently C 1-6 alkyl), an ammonium salt of formula (R3 R 4 R 5 R6 N +) m X- p (wherein R 3, R 4, R 5 and, (b) reacting a compound of formula (II) with 4,6-dichloropyrimidine in the presence of a suitable base in an environment which is substantially free of methanol, wherein W is CH 3 0 2 CCHCH(OCH 3)2 or CH 302WCH.OCH 3, and M is a metal or other suitable counterion.

3. A process for the preparation of thp compound (I):

N':: 1 N cl 0 (I) W the process comprising reacting a compound of formula (III):

I (Ili) MO "'P W with 4,6-dichloropyrimidine in an environment which is substantially free of methanol, wherein W is CH 3 0 2 CCHCH(OCH 3)2 and M is a metal or other suitable counterion.

A process for the preparation of a compound of formula (I):

N 1 N i W (1) wherein W is CH3 0 2 CCHCH(OCH 3)2 or CH 302CC CH.OCH 31 the process comprising the steps:

(a') reacting a compound of formula (IV): OCH 3 1 UN I I 'zz 0 0 (IV) and R6 are, independently C 1-6 alkyl or benzyl, X- is hydroxide, chloride, bromide, nitrate or suiphate, anil m and p fulfill valency requirements), or a nitrogen containing polycyclic ring system.

7. A process as claimed in claim 6 wherein the base is potassium carbonate, potassium bicarbonate, triethylamine, 1[,11diisopropylethylamine, imidazole, 4-(dimethylamino)pyridine, benzyltrimethylammonium hydroxide or 1,4-diazabicyclo[2,2,2]octane.

8. A process substantially as hereinbefore described with reference to the examples.