GB2097791A - Quaternary ammonium salt - Google Patents

Quaternary ammonium salt Download PDF

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Publication number
GB2097791A
GB2097791A GB8212434A GB8212434A GB2097791A GB 2097791 A GB2097791 A GB 2097791A GB 8212434 A GB8212434 A GB 8212434A GB 8212434 A GB8212434 A GB 8212434A GB 2097791 A GB2097791 A GB 2097791A
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United Kingdom
Prior art keywords
benzyl benzoate
lignocaine
lignocaine benzyl
hydrate
anhydrous
Prior art date
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Granted
Application number
GB8212434A
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GB2097791B (en
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
    • C07C29/94—Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/02—Monohydroxylic acyclic alcohols
    • C07C31/08—Ethanol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12F—RECOVERY OF BY-PRODUCTS OF FERMENTED SOLUTIONS; DENATURED ALCOHOL; PREPARATION THEREOF
    • C12F5/00—Preparation of denatured alcohol

Description

1
GB 2 097 791 A 1
SPECIFICATION Quaternary ammonium salt
This invention relates to a quaternary ammonium salt and to a process for its preparation. In particular, the invention is concerned with a process for the preparation of lignocaine benzyl benzoate. 5 Lignocaine is the approved name for N,N-diethylamino-2,6-dimethylacetanilide.
Lignocaine benzyl benzoate [benzyldiethyl(2:6-xylylcarbamoylmethyl ammonium benzoate], also known as denatonium benzoate, has the formula:—
and is described and claimed in British Patent Specification No. 955,309. It is the most bitter 10 substance known to man and is thus used where an intensely bitter taste is required for midicinal or 10 industrial purposes. It may be added to toxic substances as a deterrent to accidental ingestion and may be used as a denaturantfor alcohol.
In the final stage of preparation, the above British Specification describes in Example 1 the addition of an alcoholistic solution of benzoic acid to an alcoholic solution of lignocaine benzyl 15 hydroxide. After concentration and trituration with di-ethyl ether, the product, lignocaine benzyl 15
benzoate, is recrystallised from mixtures of ethyl acetate and isopropanol or chloroform, or from a mixture of ethanol and diisopropyl ether or from methyl ethyl ketone. An alternative preparation is described in Example 3 wherein an aqueous solution of lignocaine benzyl hydroxide is neutralised with benzoic acid, the solution is evaporated to dryness and the resulting lignocaine benzyl benzoate is 20 recrystallised from a mixture of ethanol and diisopropyl ether. 20
We have now found that lignocaine benzyl benzoate may be crystallised directly and in a high yield from solutions in water to give, initially, a lignocaine benzyl benzoate hydrate. Crystallisation of lignocaine benzyl benzoate directly from water is particularly advantageous in that it avoids the need for hazardous, inflammable organic solvents such as the ethers previously employed in the 25 crystallisation procedure which necessitated the use of flame-proof equipment in a specially designed 25 flame proof area. This aqueous crystallisation process also permits direct recovery of the compound from aqueous reaction mixtures.
Thus, according to our invention, we provide a process for the crystallisation of lignocaine benzyl benzoate which comprises agitating a solution of lignocaine benzyl benzoate in water at a 30 concentration of at least 5% w/w and at a temperature of 10 to 35°C, followed by the recovery of the 30 crystals of lignocaine benzyl benzoate hydrate thus formed.
The crystalline product is novel and thus, according to another aspect of the invention, we provide lignocaine benzyl benzoate hydrate. We have found the water content of the lignocaine benzyl benzoate hydrate to be in the range of 3.6 to 4.1% w/w.
35 According to a particular embodiment of this invention there is provided crystalline lignocaine 35 benzyl benzoate hydrate having the characteristic x-ray data substantially as herein described in Example 10 and the characteristic infra-red data as herein described in Examples 1 and 10. The water content together with the x-ray and infra-red data suggest that the product is in the form of a "wet" hemihydrate.
40 In the process according to this invention concentrations of lignocaine benzyl benzoate in water 40 of, for example, 10 to 50% w/w may be used in the crystallisation process, preferably 15 to 30% w/w and particularly about 20 to 25% w/w. These concentrations may be achieved by preparing solutions in water at an elevated temperature, for example at from 35 to 50°C, followed by cooling to the desired temperature for initiation of the crystallisation process. It is preferred to maintain temperatures of from 45 20 to 25°C throughout the crystallisation process. 45
The presence of a seed of lignocaine benzyl benzoate hydrate is preferred to induce crystallisation and it is convenient to continue agitating for from 24 to 48 hours in order to achieve an optimum yield of crystals. The crystals may be readily recovered by conventional methods (e.g. filtration or centrifugation) and may be washed, for example, with a small amount of water. The resulting crystals 50 of the hydrate may then be dried at temperatures of from 15 to 30°C, for example by forced 50
ventilation.
2
GB 2 097 791 A 2
The liquor remaining following removal of the crystals of the hydrate may be concentrated and reprocessed according to the above method to provide further crops of crystals.
According to a still further aspect of the invention we provide a process for the conversion of lignocaine benzyl benzoate hydrate to anhydrous lignocaine benzyl benzoate by heating the hydrate.
5 The hydrate may be heated, for example, at a temperature of from 75 to 110°C, preferably from 5 90 to 110°C in order to obtain the anhydrous lignocaine benzyl benzoate.
Inorganic or organic substances, preferably ethyl alcohol can be denatured, i.e. rendered unpotable or inedible, by dissolving in or mixing with them a minor proportion of lignocaine benzyl benzoate. According to the present invention the lignocaine benzyl benzoate may be used for the
10 purpose of denaturing substances, especially ethyl alcohol, in the form of the lignocaine benzyl 10
benzoate hydrate or in the form of anhydrous lignocaine benzyl benzoate prepared by heating the hydrate.
The lignocaine benzyl benzoate, in the anhydrous or hydrated form, may be incorporated in the organic or inorganic substances in minor proportions as described in British Patent Specification No.
15 955,309. For example, concentrations of less than 0.01% by weight of the lignocaine benzyl benzoate 15 are generally sufficient to denature the substance in which it is incorporated. The bitterness is apparent at concentrations as low as 0.0005% by weight. In the case of ethyl alcohol, a concentration of about 0.005% by weight of the lignocaine benzyl benzoate may generally be employed; the preferred concentration being from 0.01% to 0.001% by weight.
20 According to the invention, the lignocaine benzyl benzoate hydrate, or the anhydrous lignocaine 20 benzyl benzoate prepared therefrom, may conveniently be used in the form of an aqueous solution having a concentration of, for example, 0.1 to 5% by weight.
The following Examples illustrate the invention. All temperatures are in °C.
Example 1
25 Lignocaine benzyl benzoate (20 g) was dissolved in deionised water (80 g) with stirring and 25
warming to 40°. The resulting solution (20% w/w) was cooled to 20° in a cold water bath and stirred magnetically for 24 hours. The product was obtained as a fine white, crystalline solid which was filtered off and washed with deionised water (20 ml). The damp cake was dried in a dish by forced ventilation at 20° until weight loss was minimal, to yield crystals of lignocaine benzyl benzoate hydrate
30 (15.74 g); v max (KBr discs) 1688 (> C=0), 1 535, 1475, 1270, 865 and 808 cm-1. 30
Example 2
A sample of the lingocaine benzyl benzoate hydrate obtained in Example 1 (1.04 g) was further dried at 105° to constant weight to yield anhydrous lignocaine benzyl benzoate (0.99 g) identical to an authentic sample; v max (KBr discs) 1680 (> C=0), 1400, 880, 735 and 610 cm-1.
35 Example 3 35
Lignocaine benzyl benzoate (20 g) was dissolved in water (100 g) at 40° and was cooled to room temperature. A seed of lignocaine benzyl benzoate hydrate was added and the solution (17% w/w) was stirred at between 15 and 25° for 27 hours. The product was recovered and dried by the methods of Example 1 to yield lignocaine benzyl benzoate hydrate (15.8 g).
40 The filtrate was concentrated and crystallised in a similar manner to yield a further crop of.
lignocaine benzyl benzoate hydrate (2.8 g).
Example 4
A 10% w/w solution of lignocaine benzyl benzoate in deionised water (200 g total weight) was prepared with stirring and warming to 35°. The solution was filtered through a porosity 3 sintered
45 glass filter funnel to remove insoluble matter and was cooled to 20° before seeding with lignocaine 45 benzyl benzoate hydrate. Stirring was maintained at 20° for 24 hours and the lignocaine benzyl benzoate solid jvas then filtered off, drained, and dried to constant weight by forced ventilation at 15— 20° to give lignocaine benzyl benzoate hydrate.
Example 5
50 Lignocaine benzyl benzoate (30.0 g) was dissolved in deionised water (70.0 g) with stirring and 50 warming to 35°. The resulting 30% w/w solution was cooled, seeded with lignocaine benzyl benzoate hydrate and stirred at 20° for 24 hours. The resulting solid was filtered off and dried by forced ventilation at ambient temperature to give lignocaine benzyl benzoate hydrate (25.97 g).
Example 6
55 A 20% w/w aqueous solution was prepared from lignocaine benzyl benzoate (20.0 g) and 55
deionised water (80.0 g) with stirring and warming to 35°. After filtration through a porosity 3 sintered glass filter funnel the solution was stirred at 35—37° for 24 hours. The solution was seeded with lignocaine benzyl benzoate hydrate and stirred for a further 24 hours at 35°. The small amount of white crystalline solid which had separated was filtered off, drained and dried at ambient temperature
60 to constant weight to give lignocaine benzyl benzoate hydrate. 60
3
GB 2 097 791 A 3
Example 7
The product of Example 4 was further dried at 106° for two hours to yield anhydrous lignocaine benzyl benzoate (11.05 g).
Example 8
5 The lignocaine benzyl benzoate hydrate obtained in Example 5 was further dried at 106° for 3\ hours to give anhydrous lignocaine benzyl benzoate (24.94 g).
Example 9
The product of Example 6 was further dried at 106° to constant weight to yield anhydrous lignocaine benzyl benzoate (0.55 g).
10 Example 10
Lignocaine benzyl benzoate (100 g) was dissolved in deionised water (300 g) with stirring and warming to 40°. The resulting solution (25% w/w) was filtered through a sintered glass funnel and seeded with lignocaine benzyl benzoate hydrate. The solution was cooled to 20°C in a cold water bath and stirred magnetically for 24 hours. The product was obtained as a fine white, crystalline solid which 15 was filtered off and washed with deionised water (100 ml). The damp cake was dried in a dish by forced ventilation at ambient temperature until weight loss was minimal, to yield crystals of lignocaine benzyl benzoate hydrate (83.3 g); v max (Nujol (Registered Trade Mark) Mull) 3436 s, 2770 s, 1694 s, 1648 w, 1608 s, 1596 s, 1574 s, 1568 sh, 1538 s, 1498 w, 1408 w, 1312 m, 1288 m, 1272 m, 1252 m, 11 60 w, 1030 w, 782 s, 758 m, 724 s, 704 s and 676 s cm-1.
20 sh=shoulder, s=strong, m=medium, w=weak.
The X-ray diffraction pattern of lignocaine benzyl benzoate hydrate may be obtained by loading the material into a 0.3 mm diameter glass capillary and photographing the patterns by the Debye Scherrer method in a 114.6 mm diameter camera by exposure for 12 hours to CoKa radiation and for 3 hours to CuK„ radiation. The weighted mean values of X-ray wavelengths used for the calculations 25 were CuK„=1.54171A and CoKa=1.79024A.
The X-ray diffraction pattern of a sample of lignocaine benzyl benzoate hydrate prepared by the method just described in terms of'd' spacings and intensities of the lines is given in the following Table.
Table
30
d(k)
Intensity d(k)
Intensity
13.92
m
3.30
w
10.83
m
3.19
vw
9.71
s
3.11
m
7.70
m
2.93
wd
35
7.02
s
2.79
wd
5.82
m
2.72
w
5.45
s
2.58
vw
5.21
m
2.47
vw
4.82
ms
2.41
vw
40
4.71
w
2.37
vw
4.33
m
2.30
w
4.21
w
2.12
vw
3.90
vs
2.04
w
3.73
w
1.99
vw
45
3.63
m
1.94
vw
3.54
m
1.86
vw
3.37
m
1.84
w s=strong; m=medium; w=weak; v=very; d=diffuse.

Claims (1)

  1. Claims
    50 1 ■ Lignocaine benzyl benzoate hydrate.
    2. Crystalline lignocaine benzyl benzoate hydrate.
    3. Crystalline lignocaine benzyl benzoate hydrate according to claim 2, having the characteristic infra-red data substantially as herein described in Example 1.
    4. Crystalline lignocaine benzyl benzoate hydrate according to Claim 2, having the characteristic 55 infra-red and X-ray data substantially as herein described in Example 10.
    5. A process for the crystallisation of lignocaine benzyl benzoate which comprises agitating a solution of lignocaine benzyl benzoate in water at a concentration of at least 5% w/w and at a temperature of 10 to 35°C and recovering the resulting crystals of lignocaine benzyl benzoate hydrate.
    5
    10
    15
    20
    25
    30
    35
    40
    45
    50
    55
    4
    GB 2 097 791 A 4
    6. A process according to Claim 5, wherein the solution of lignocaine benzyl benzoate in water is a 10 to 50% w/w solution.
    7. A process according to Claims 5 or 6, wherein the temperature is maintained at 20 to 25°C.
    8. A process for the conversion of lignocaine benzyl benzoate hydrate to anhydrous lignocaine
    5 benzyl benzoate which comprises heating the hydrate and recovering anhydrous lignocaine benzyl 5
    benzoate.
    9. A process according to Claim 8 wherein the hydrate is heated at a temperature of from 75°C to 110°C.
    10. Anhydrous lignocaine benzyl benzoate when prepared by a process according to Claim 8 or 9.
    10 11. A process for the preparation of lignocaine benzyl benzoate which comprises agitating a 10
    solution of lignocaine benzyl benzoate in water at a concentration of at least 5% w/w and at a temperature of 10°C to 35°C, recovering the resulting crystals of lignocaine benzyl benzoate hydrate,
    heating the resulting crystals and recovering anhydrous lignocaine benzyl benzoate.
    12. Lignocaine benzyl benzoate when prepared by a process according to Claim 11.
    15 13. A method of denaturing an inorganic or organic substance which comprises mixing therewith 15
    or dissolving therein a minor proportion of lignocaine benzyl benzoate hydrate.
    14. A method of denaturing an inorganic or organic substance which comprises mixing therewith or dissolving therein a minor proportion of anhydrous lignocaine benzyl benzoate according to Claim 10 or 12.
    20 15. A method of denaturing an inorganic or organic substance according to Claim 13 or 14 20
    wherein the minor proportion is from 0.01% to 0.001% by weight.
    16. A method according to any of Claims 13 to 15 wherein the organic substance is ethyl alcohol.
    17. An inorganic or organic substance which has been denatured by the incorporation therein of a minor proportion of lignocaine benzyl benzoate hydrate.
    25 18. An inorganic or organic substance which has been denatured by the incorporation therein of a 25 minor proportion of anhydrous lignocaine benzyl benzoate according to Claim 10 or 12.
    19. Ethyl alcohol which has been denatured according to Claim 17 or 18.
    20. An aqueous solution of lignocaine benzyl benzoate hydrate according to any of Claims 1 to 4.
    21. An aqueous solution according to Claim 20, having a concentration of the hydrate of 0.1 to
    30 5% by weight. 30
    22. An aqueous solution of lignocaine benzyl benzoate according to Claim 10 or 12.
    23. An aqueous solution according to Claim 22 having a concentration of the benzoate of 0.1 to 5% by weight.
    Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1982. Published by the Patent Office.
    25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.
GB8212434A 1981-04-30 1982-04-29 Quaternary ammonium salt Expired GB2097791B (en)

Applications Claiming Priority (2)

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GB8113416 1981-04-30
GB8124864 1981-08-14

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GB2097791B GB2097791B (en) 1984-08-01

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US (1) US4438046A (en)
AU (1) AU548251B2 (en)
CA (1) CA1196928A (en)
CH (1) CH653010A5 (en)
DE (1) DE3215987A1 (en)
FR (1) FR2504922B1 (en)
GB (1) GB2097791B (en)
IT (1) IT1147862B (en)
NL (1) NL8201797A (en)
SE (1) SE8202713L (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015495A1 (en) * 1997-09-19 1999-04-01 Burlington Bio-Medical & Scientific Corp. Denatonium capsaicinate and methods of producing the same

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5776859A (en) * 1995-11-15 1998-07-07 Nickel; Alfred A. Sodium channel active novel compounds and related processes and bioassay techniques
DE19714580A1 (en) * 1997-04-09 1998-10-15 Haarmann & Reimer Gmbh Denaturant for ethanol
US7011843B2 (en) * 1997-10-01 2006-03-14 Lts Lohmann-Therapie Systeme Ag Method for protecting a human being against health impairment by ingestion of a transdermal therapeutic system
US7632321B2 (en) * 2001-11-01 2009-12-15 Idatech, Llc Fuel processing systems, fuel cell systems, and improved feedstocks therefor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3080326A (en) 1959-06-01 1963-03-05 T & H Smith Ltd Denatured alcohol
GB955309A (en) * 1959-11-20 1964-04-15 Edinburgh Pharmaceutical Ind L New quaternary salts and compositions containing them
US3080327A (en) 1959-11-20 1963-03-05 T & H Smith Ltd Quaternary salts as denaturants for organic substances

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015495A1 (en) * 1997-09-19 1999-04-01 Burlington Bio-Medical & Scientific Corp. Denatonium capsaicinate and methods of producing the same

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DE3215987A1 (en) 1982-12-02
US4438046A (en) 1984-03-20
GB2097791B (en) 1984-08-01
SE8202713L (en) 1982-10-31
NL8201797A (en) 1982-11-16
CA1196928A (en) 1985-11-19
CH653010A5 (en) 1985-12-13
FR2504922A1 (en) 1982-11-05
IT1147862B (en) 1986-11-26
AU548251B2 (en) 1985-12-05
AU8313582A (en) 1982-11-04
IT8248305A0 (en) 1982-04-29
FR2504922B1 (en) 1985-11-22

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