GB2200111A - Process for the preparation of a symmetrical combined ester of glycerol - Google Patents
Process for the preparation of a symmetrical combined ester of glycerol Download PDFInfo
- Publication number
- GB2200111A GB2200111A GB08728203A GB8728203A GB2200111A GB 2200111 A GB2200111 A GB 2200111A GB 08728203 A GB08728203 A GB 08728203A GB 8728203 A GB8728203 A GB 8728203A GB 2200111 A GB2200111 A GB 2200111A
- Authority
- GB
- United Kingdom
- Prior art keywords
- glycerol
- preparation
- process according
- chlorophenoxy
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the preparation of an antiatherosclerotic agent (I) which is obtained on reaction of p-chlorophenoxy-isobutyric acid (II) with 1,3-dichloropropanol (III) in the presence of a condensation agent and further reaction of the intermediate ester (IV) obtained with an alkaline salt of nicotinic acid, in the presence of a phase transfer catalyst.
Description
Process for the Preparation of a
Symmetrical Combined Ester of Glycerol
This invention relates to a process for the preparation of a symmetrical combined ester of glycerol, glycerol-2 -p-chlorophenoxy-isobutyrate-1 , 3-dinicotinate, as per
Formula I:
Compound I is an effective agent in preventing and treating atherosclerosis and the consequences thereof, in cerebral, coronary and peripheral vascular disorders, thanks to its normolipemiant, anticholesterolemic and microhemorheological action.
This latter property distinguishes it from hypolipemiant agents, which lack it. Its dual mechanism of action gives Compound I a definite advantage in the fight against atherosclerosis.
From Spanish Patent No. 463,218 a method is known for obtaining Compound I, based on the -following two stages:
Stage One
Esterification of 2- (4-chlorophenoxy) -isobutyric acid (II) with 1,3-dichloro-2-propanol (III) to yield the intermediate substance (IV):
This esterification is carried out by acid catalysis, using sulphuric acid, for example.
Stage 2
Reaction of the intermediate substance IV with 2 moles of an alkaline salt of nicotinic acid (for example, sodium nicotinate):
This substitution reaction is typically carried out by using dimethylformamide as a solvent at the reflux temperature of the system.
This process, however, has these disadvantages: 1. Stage 1 requires long reaction times, typically of
48 h.
2. Such a long required time, together with the fact
that an acid catalyst is needed at relatively high
temperatures, translates into resin formation,
resulting in an impure substance IV.
This is a particularly important point sunce
intermediate substance IV is a non-distillable
liquid and is consequently very difficult to
purify.
3. In Stage 2, the relative insolubility of the
alkaline salts of nicotinic acid determines the
need for high temperatures, typically around
1500C, which entails the formation of resins and
impedes the isolation and purification of Compound
I.
It has been found that, if Stage 1 is carried out without using acid catalysts such as sulphuric acid, an intermediate substance IV of high purity is obtained.
This is achieved with the use of a condensation agent such as p-toluene-sulphonyl chloride, and the use of a base such as pyridine, as a catalyst, under certain conditions preventing the formation of alcohol III tosylate as a by-product.
It has also been found that, in Stage 2, the use of phase transfer catalysts such as tetrabutylammonium bromide, allows the heat level required for the reaction to be reduced (typically from 150 0C to 90-100 C), with the resulting reduction in resin formation while allowing Compound I to be precipitated from the reaction crude with a high purity.
All this provides an increase in average efficiency from 46% (as per Spanish Patent No. 463,218) to 65%.
The reaction time decreases from 52 hours (Spanish
Patent No. 463,218) to 10 hours.
The process that is the object of this invention consequently consists of reacting p-chlorophenoxyisobutyric acid (II),
with 1,3-dichloropropanol (III),
in the presence of a condensation agent such as trifluoracetic anhydride ((CF3CO) 20) or a sulphonyl chloride of general formula R-SO2C1 (where R may be
and a tertiary amine such as pyridin or triethylamine, to yield 1,3-dichloro-propyl-2-p-chlorophenoxyisobutyrate (IV),
and of reacting the intermediate Compound IV with an alkaline salt of nicotinic acid, in the presence of a phase transfer catalyst such as tetrabutylammonium bromide or triethylbenzylammonium chloride, to prqduce Compound I.
The invention will now be described by way of example.
Example 1
Phase 1. Preparation of intermediate substance IV.
In a 500ml flask equipped with magnetic agitation and reflux cooling, place 21.45g (0.1 Mole) p-chlorophenoxy -isobutyric acid, 12.90g (0.1 Mole) 1,3-dichloropropanol, 16.00g (0.2 Mole) pyridine, 19.07 (0.1 Mole) p-toluenesulphonyl chloride and 100 ml toluene.
The system is ref fluxed for 5 h. Allow to cool, wash with water, dilute hydrochloric acid and water, and agitate the organic phase with 150 ml 10% ammonia for 10 minutes. It is then decanted and washed with water, and the solvent is evaporated.
31.50g viscous yellowish liquid is obtained which is used in the following step without further purification.
Yield: 97%.
IR: 1740, 1585, 1485, 1375, 1235
Phase 2. Preparation of Compound I.
In a 250ml flask equipped with magnetic agitation and reflux cooling, place 20.00g (63 mMole) of intermediate substance IV, 19.00g (130 mMole) anhydrous sodium nicotinate, 4.00g triethylbenzyl-ammonium chloride, 20ml dimethylformamide and 8ml acetonitrile. The system is refluxed for 5 h. Allow it to cool and add 40ml water. Agitate for 2 h at ambient temperature, filter and recrystallize with methanol.
20.77g white solid is obtained.
Yield: 66% m.p.: 99-100 C.
IR: 1745, 1720, 1590, 1485, 1390, 1370, 1235.
Example 2
Phase 1: Preparation of intermediate substance IV.
In a 500ml flask equipped with magnetic agitation and reflux cooling, place 21.45g (0.1 Mole) p-chlorophenoxy-isobutyric acid, 12.90g (0.1 Mole) 1,3-dichloropropanol, 24.00g (0.3 Mole) pyridine, 11.75g (0.1 Mole) methanesulphonyl chloride and lOOmi chloroform.
The system is ref fluxed for 6 h. Allow it to cool, wash with water, dilute hydrochloric acid and water, and evaporate the solvent.
28.40g is obtained.
Yield: 90%
Phase 2. Preparation of Compound I
In a 250ml flask, place 12.50g (0.1 Mole) nicotinic acid, 6.60g (0.1 Mole) 85% potassium hydroxide and 10 ml water. Once a clear solution has been obtained, 3 aliquots of 20ml dimethylformamide are added, evaporating to dryness under reduced pressure each time.
Add 15.00g 90.046 Mole) intermediate substance IV, 3.00g tetrabutylammonium bromide, 20ml dimethylformamide and 9ml acetonitrile. Reflux for 4 h.
Isolate the produce as in the previous example.
15.85g are obtained.
Yield: 69% m.p. 99-1000C.
Claims (6)
1. A process for preparation of a symmetrical combined ester of glycerol, glycerol-2-p-chlorophenoxy- isobutyrate-1,3-dinicotinate (I), characterised in that p-chlorophenoxy-isobutyric acid (II)
is reacted with 1,3-dichloropropanol (III),
in the presence of a condensation agent and a tertiary amine, to yield 1, 3-dichloropropyl-2-p-chlorophenoxyisobutyrate (IV),
and the intermediate compound IV is reacted with an alkaline salt of nicotinic acid, in the Sresence of a phase transfer catalyst to produce compound I.
2. A process according to Claim 1 in which the condensation agent comprises trifluoroacetic anhydride ((CF3CO)20) or a sulphonyl chloride having the general formula R-S02C1 in which R is alkyl, aryl or aralkyl.
3. A process according to Claim 2 in which R is CH3-,
4. A process according to any of Claims 1 to 3, in which the tertiary amine comprised pyridine or triethylamine.
5. A process according to any preceding claim, in which the phase transfer catalyst comprises tetrabutylammonium bromide or triethylbenzylammonium bromide.
6. A process substantially as hereinbefore described with reference to the examples.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES8603309A ES2003964A6 (en) | 1986-12-05 | 1986-12-05 | Process for the preparation of a symmetrical combined ester of glycerol |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8728203D0 GB8728203D0 (en) | 1988-01-06 |
GB2200111A true GB2200111A (en) | 1988-07-27 |
GB2200111B GB2200111B (en) | 1990-05-23 |
Family
ID=8248851
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8728203A Expired - Fee Related GB2200111B (en) | 1986-12-05 | 1987-12-02 | Process for the preparation of a symmetrical combined ester of glycerol |
Country Status (5)
Country | Link |
---|---|
DE (1) | DE3740166A1 (en) |
ES (1) | ES2003964A6 (en) |
GB (1) | GB2200111B (en) |
IT (1) | IT1211569B (en) |
PT (1) | PT86214B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006058199A1 (en) * | 2004-11-23 | 2006-06-01 | Fazix Corporation | Methods of modulating high-density lipoprotein cholesterol levels and pharmaceutical formulations for the same |
-
1986
- 1986-12-05 ES ES8603309A patent/ES2003964A6/en not_active Expired
-
1987
- 1987-11-25 PT PT86214A patent/PT86214B/en not_active IP Right Cessation
- 1987-11-26 DE DE19873740166 patent/DE3740166A1/en not_active Withdrawn
- 1987-12-01 IT IT8768032A patent/IT1211569B/en active
- 1987-12-02 GB GB8728203A patent/GB2200111B/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006058199A1 (en) * | 2004-11-23 | 2006-06-01 | Fazix Corporation | Methods of modulating high-density lipoprotein cholesterol levels and pharmaceutical formulations for the same |
Also Published As
Publication number | Publication date |
---|---|
IT8768032A0 (en) | 1987-12-01 |
ES2003964A6 (en) | 1988-12-01 |
PT86214B (en) | 1990-11-07 |
GB8728203D0 (en) | 1988-01-06 |
PT86214A (en) | 1987-12-01 |
IT1211569B (en) | 1989-11-03 |
DE3740166A1 (en) | 1988-06-16 |
GB2200111B (en) | 1990-05-23 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19931202 |