JPS63126873A - 4-bromomethyl-5-methyl-1,3-dioxolen-2-one - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula. USE:A modifying agent for prodrugs which are medicines and introducing reagent for protecting groups in chemical reaction. PREPARATION:4,5-Dimethyl-1,3-dioxolen-2-one is reacted with a brominating agent in a molar amount of 0.8-1.2 times, normally 1.0-1.2 times at room temperature or generally under radial forming and heating condition to afford the compound expressed by the formula. The above-mentioned compound is capable of readily reacting with carboxylic acids, thiocarboxylic acids, phenols, etc., to form the corresponding ester type or ether type compounds. Although such compounds are stable in neutral and acidic media, readily hydrolyzed under alkaline hydrolytic condition in ordinary chemical reactions, the compounds are relatively stable in alkaline media corresponding to intestinal juice and readily hydrolyzed in the presence of in vivo enzymes and restored to the original compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 4-bromomethyl-5-methyl-1°3-dioxolen-2-ones useful as modifiers for pharmaceutical prodrugs.

Although some drugs have high pharmacological activity, they have chemical instability and bioavailability (bioavailability).
There are some drugs that cannot fully demonstrate their usefulness as pharmaceuticals due to poor quality, etc., and one way to improve these drawbacks is to create prodrugs by chemical modification.

For example, a drug with a low rate of intestinal absorption is chemically partially modified to increase its absorption in the intestinal tract and to express its inherent chemical and biological pharmacological activity in vivo.

Various modification groups have been proposed for this purpose, but the chemical stability of prodrugs using them,
The level of satisfaction has not yet been reached in terms of reconstitution properties in vivo to the original drug, side effects caused by modifying groups, etc.

The present invention provides a novel 4-bromomethyl-5 compound represented by the following formula, which is particularly useful as a modifier for prodrugs of pharmaceuticals.
-Methyl-1,3-dioxolen-2-one.

This 4-bromomethyl-5-methyl-1,3-dioxolen-2-one is a carboxylic acid, a thiocarboxylic acid,
It easily reacts with phenol, etc. to produce corresponding ester-type compounds and ether-type compounds, but these ester-type compounds and ether-type compounds are stable in neutral and acidic media, and are resistant to alkali in normal chemical reactions. Although it is easily hydrolyzed under hydrolytic conditions, it is relatively stable in an alkaline medium equivalent to intestinal fluid, and is easily hydrolyzed and restored to its original compound in the presence of in vivo enzymes. do.

For example, when a penicillin having a carboxylic acid group is reacted with 4-bromomethyl-5-methyl-1,3-dioxolen-2-one represented by the above formula, a corresponding ester is produced, and this ester is present in gastric and intestinal fluids. It is stable, easily absorbed from the intestinal tract, and easily hydrolyzed in vivo to restore the original penicillin. In this way, 4-bromomethyl-5-methyl-1,3 represented by the above formula
-Dioxolen-2-one is particularly useful as a modifier for pharmaceutical prodrugs. As mentioned above, the carboxylic acids, phenols, and esters and ethers derived from 4-bromomethyl-5-methyl-1,3-dioxolene-2=one of the present invention are stable in neutral and acidic media. However, since it is easily hydrolyzed under normal alkaline hydrolysis conditions, the 4-bromomethyl-5-methyl-1,3-dioxolene-2-
ions are also useful as reagents for introducing protective groups in chemical reactions.

The following is experimental data demonstrating the usefulness of the present invention.

[Blood concentration during oral administration] 1. Test compound A ampicillin (5-methyl-2-oxo-1゜3-
dioxolen-4-yl) methyl ester hydrochloride (Synthesized from ampicillin trihydrate and 4-bromomethyl-5-methyl-1,3-dioxolen-2-one according to Reference Example 1 described below.) B Ampicillin phthalidyl Ester hydrochloride (known ampicillin ester, control compound) C ampicillin trihydrate (control compound) 2, test method 4-week-old mice fasted overnight (ddY strain, weight 202,
Ampicillin equivalent: 50.0 mg/kg per group of 5 animals)
Equivalent test compound (concentration 5 wni in terms of ampicillin)
/ml of an aqueous solution of about 0.2 mjl> was orally administered, blood was collected over time, the ampicillin concentration in the serum was measured by a bioassay method, and the relative ratio of ampicillin concentration in the serum of each test compound was determined.

3. Results 1 As is clear from Table 1, ampicillin ester (A) derived from the compound of the present invention is easily absorbed and restored to the original ampicillin in vivo, but ampicillin (C) and higher hydrolysis in an acidic medium (corresponding to artificial gastric fluid) over a long period of time than known ampicillin esters (B) 1. Test compound A and B above 2. Test method 10100 O salt in water 2. Og, 10% hydrochloric acid 24
ml, acidic medium (pH 1,2) containing 3.2 g of pepsin
The test compound was dissolved in the solution, sampled over time while shaking at 37°C, and the hydrolysis rate was determined from the decrease in peak height of each test compound using high performance liquid chromatography using a reversed phase partition column. .

3.Results Table 2 As shown in Table 2, A has a lower W− than B in acidic medium.
It is stable.

[Hydrolysis in basic medium (corresponding to artificial intestinal fluid)] 1.
Test compound A and B above 2. Test Method 1000 - Disodium Phosphate in Water 35.82.10
The test compound was dissolved in a basic medium (pH 7.5) containing % hydrochloric acid 6.0aN and pancreatin 2.82%, and the hydrolysis rate of each test compound was determined in the same manner as in the case of the acidic medium. I asked for it.

3. Results Table 3 As shown in Table 3, A is more stable than B in a basic medium.

[Others] The toxicity (L D s.) of the above A was tested in mice (4 weeks old ddY
The results of the investigation using the system) are as follows.

Oral administration > 5,000 mg/kg, intraperitoneal administration 1.43
0 mg/kg, intravenous administration 557 mg/kg.

As described above, the 4-bromomethyl-5-methyl-
Although 1,3-dioxolen-2-one is extremely useful as a modifier for pharmaceutical prodrugs, such usefulness cannot be predicted from conventional knowledge. That is, 4,5-dimethyl-1,3-dioxolen-2-one, which is a precursor of the compound of the present invention, is converted into tetrahedron.
Letters, 1972, pp. 1701-1704, but there is no description of the compounds of the present invention derived therefrom. 4,
By brominating 5-dimethyl-1,3-dioxolen-2-one, 4, which is an intermediate raw material for polymer production, is produced.
5-bis(bromomethyl)-1,3-dioxolene-2
It is stated that -on can be obtained. However, this document does not contain any specific description regarding the compound of the present invention or its production method, nor does it provide any suggestion regarding its use.

The 4-bromomethyl-5-methyl-1゜3-dioxolen-2-one of the present invention can be added to 4,5-dimethyl-1,3-dioxolene-2-one under radical generation conditions at room temperature or generally under heating conditions. 0.8 to 1.2 mol, usually an equimolar amount or an excess (160 to 1.2 times mol) of the brominating agent.

The starting material 4,ra-dimethyl-1,3-dioxolen-2-one was obtained from the aforementioned Tetrahedron Letters, 1.
972, pp. 1701-1704.

Examples of the brominating agent include bromine, N-bromophthalimide, N-bromosuccinimide, and the like. Starting material 4,5-dimethyl-1,3-dioxolene-2-
In order to proceed with the reaction between the on and the brominating agent, irradiation with external radiation during the reaction is carried out.
-+P*〆shi+ 1 no 1 no iA-t+ -L
I+ +1 It is preferable to use a radicalizing agent such as benzoyl peroxide. The reaction solvent is selected appropriately depending on the properties of the raw materials, such as methylene chloride, chloroform, carbon tetrachloride, ethylene tetrachloride, benzene. etc.

The present invention will be specifically explained below with reference to Examples and Reference Examples.

Example 1 Preparation of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one 4.5-dimethyl-1,3-dioxolene-2-one (
Tetrahedron Letters, 1972, 1701-1
3,422 (synthesized according to page 704) with carbon tetrachloride 1
To this was added N-bromosuccinimide of 5°342 and α,α'-azobisisobutyronitrile as a catalyst, and the reaction solution was heated under reflux for 15 minutes and concentrated to half its volume to remove insoluble matter. After removing the liquid, the furnace liquid was concentrated. Distillation of the slag-like residue under reduced pressure yields a colorless liquid with a boiling point of 115-12
0 °C/5 m m Hg target material 4.2 & (yield 73
%) was obtained.

Elemental analysis (%), molecular formula C5HsBrOs: theoretical value C1
31,12:H12,61:Br, 41,40° Experimental value C131,30:H52,49:Br, 41.31°IR, vcm-'>: around 1825 (carbonyl) NMR (CCN, ) δ (PPm): 2.10 (CH3,
s), 4.10 (CH2Br, s) Reference Example 1 500 mg of ampicillin trihydrate was dispersed in 6 ml of dimethylformamide, and 126 mg of potassium bicarbonate was added thereto.
was added, cooled to 0°C, and further added 0.25% of benzaldehyde.
ml was added and stirred at 0°C for 2.5 hours. Next, potassium bicarbonate 125rin8 and 4-bromomethyl-5-methyl-1
, 250 mg of 3-dioxolen-2-one was added and further 0
Stirred at ℃ for 3 hours.

After the reaction, the reaction solution was poured into ice water, the precipitated solid was extracted with 30 ml of ethyl acetate, and the organic layer was poured into 20 ml of water.
After washing with water three times and drying with anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure to obtain a yellow syrup.

The slag-like residue obtained as above was dissolved in acetonitrile 4, adjusted to pH 2.0 with dilute hydrochloric acid, and heated to 30°C at 0°C.
Stir for a minute. 10 ml of water was added to this, the acetonitrile was distilled off under reduced pressure, and the aqueous layer was washed repeatedly with ethyl acetate, then saturated with common salt, and the precipitated oily substance was extracted with methylene chloride (5 ml).
It was extracted with 0ml and washed with saturated saline. The methylene chloride solution was concentrated to half the volume of drying over anhydrous sodium sulfate, 30 ml of isopropyl alcohol was added, and the mixture was concentrated again under reduced pressure to obtain a pale yellow solid.

This solid was washed with FM, isopropyl alcohol and ether, and ampicillin (5-methyl-2-oxo-1,3
-dioxolen-4-yl) methyl ester hydrochloride was obtained.

Yield 50.6%, colorless amorphous solid.

It begins to color at a melting point of 141°C and foams at 145°C.

IR (KBr, l/C11-'): 1825.17
85.1750.1690 (carbonyl) Elemental analysis (C21H23N 307 S-HC1・H2
O), calculated value: C148, 8: H2S, 08: N, 8.
14, S, 6.21. Experimental value: C, 48, 51: H2
S.

15:N, 8.02, S, 6.44゜This ampicillin (5-methyl-2-oxo-1,3-
dioxolen-4-yl) methyl ester hydrochloride 40
After incubating in mouse blood for 15 minutes at 37°C, bioautodurum was performed, and the product was completely converted to ampicillin.

2 others

Claims (1)

[Claims] 4-Bromomethyl-5-methyl-1,3-dioxolen-2-one.