JPS58150585A - Preparation of 1,3-dioxolen-2-one derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formulaI(R1 is H, lower alyl, or aryl; R2 is H or R2 and R1 are linked to carbon chain in cyclic state; X is halogen). EXAMPLE:4-Chloromethyl-1,3-dioxolen-2-one. USE:Useful especially as a modifying agent for a prodrug of a medicine. PROCESS:A compound shown by the formula II is reacted with preferably 0.8- 1.2mol halogenating agent (e.g., Cl, Br, etc.) at room temperature or usually under conditions to produce a radical under heating, to give a compound shown by the formulaI. Ultraviolet light is irradiated during the reaction, or a free- radical initiator such as alpha,alpha'-azobisisobutyronitrile, etc. is added to the reaction system, so that the reaction is preferably promoted. An ester and an ether derived from the compound shown by the formulaIare stable in a neutral medium, but it is easily hydrolyzed under common alkali hydrolyzing conditions, so it is useful as a reagent for introducing a protecting group in chemical reactions.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel 1,3-dioxolen-2-one derivatives useful as modifiers for prodrugs of pharmaceuticals.

Among pharmaceuticals, FcFi is a substance that has high pharmacological activity but cannot fully demonstrate its usefulness as a pharmaceutical due to chemical instability or poor bioavailability. However, one way to improve these drawbacks is through chemical modification! There is a rod drug.

For example, a drug with a low intestinal absorption rate can be partially modified chemically to increase intestinal v absorption, and then restored to its original state in vivo through chemical and biological action P+i, thereby preserving the original Jlkl properties of the drug. This is the way to express it.

Various modification groups have been proposed for this purpose, but the chemical stability of zolodrugs using them,
The level of satisfaction has not yet been reached in terms of the reversibility of biogenic acetate to the original drug, and the side effects caused by modifying groups.

The present invention provides 1,S-dioxolene-! represented by the general formula CI], which is particularly useful as a modifier for zolodrugs of pharmaceuticals. -Production method of -one derivative [In the formula, R1 represents a hydrogen atom, a lower alkyl group or an aryl group, and represents an XFi halo r atom. R1 is a hydrogen atom or is cyclically bonded to R1 through a carbon chain] 1,3-dioxolen-2-one conductor L1 represented by the general formula [Natsu] is a new compound that has not been described in any literature. ,
Specific examples include 4-chloromethol-1,3-dioxolen-2-one, 4-bromomethyl-1,3-dioxolen-2-one, 4-chloromethy-5-methyl-1,
3-Dioxolen-2-one, 4-bromomethyl-5-
) fl, 3-dioxolen-2-one, 4-iodomethyl-5-methyl-1,3-dioxolen-2-one, 4-chloromethyl-5-phenyl-1゜a-dioxolen-2-one, 4-/tetramomethyl=5-phenyl-1
．． 3-Dioxolen-2-one, 3-chloro-1,2-
Carbonyldioxycyclohexene, 3-meryl 1.
These include 2-carponylzooxycyclohexene, 3-pulmo-1,2-carbonyldioxycyclooctene, and the like.

Nire et al.'s 1,3-soquinren-2-one visiting conductors all react easily with carboxylic acid catalysts, thiocarganes, and phenols to produce corresponding ester-type and ether-type compounds. However, these ester-type compounds and ether source compounds are stable in neutral and acidic media, and although they are easily hydrolyzed under alkaline hydrolysis conditions in normal chemical reactions, they do not phase into the intestinal fluid. Relatively stable in alkaline media and rarely
Moreover, in the presence of in vivo enzymes, it is easily hydrolyzed and restored to its original compound.

For example, penicillins having a carboxylic acid group and general formula [I
] The reaction of the 1,3-dioxolen-2-one I conductor produces the corresponding ester, which is stable in gastric and gastrointestinal fluids, easily absorbed from the intestinal tract, and produced. It is easily hydrolyzed in the body and restored to its original form as penicillin. In this way, l represented by the general formula [13].

3-Dioxolen-2-one derivatives are often useful as drug modifiers, especially for pharmaceuticals. In addition, carboxylic acids and phenols and the 1.3-/oxolene-2-
Esters and ethers derived from on-sieve conductors are stable in neutral media and acidic rays as described above, but they are easily hydrolyzed by Fib under normal alkali-11 water decomposition conditions. 1.3-Dioxolene-2-one sieve conductors are also useful as reagents for introducing protective groups in chemical reactions.

Below, we list experimental data showing the usefulness of 64 #l, 3-dioxolene-2-ones.

[Blood concentration during oral administration]

1. Test compound A ampicillin (5-methyl-2-oxo-1,3-
&oxocin-4-yl) methyl ester acid salt (Synthesized from ampicillin trihydrate and 4-bromomethyl-5-methyl-1°3-nooxolen-2-one according to Reference Example 3 described below.) B Ampicillin phthalate Dyl ester hydrochloride (known ampicillin ester, reference compound)
C Ampicillin trihydrate (control compound) 2 Test method: 4 withdrawal mice with 0 meals per night 1 ddY thread, weight 202
A test compound (an aqueous solution with a concentration of 5 jv/7! in terms of ampicillin, approximately 0.!-) was orally administered to ampicillin equivalents of 5 αO~/1 group (5 animals), and blood was collected over time to determine the ampicillin level in the serum. 5 concentration by bioassay method.
The relative ratio of serum ampicillin concentration of each supplied compound was determined.

3. Results 1 As is clear from Table 1, the l,3-diokiln-2
- ampicillin ester derived from one b conductor (4
is easily absorbed in vivo to form the original ampicillin IK-
Ampicillin 9 is restored and maintains a higher blood ampicillin concentration over a longer period of time than the known acipicillin ester (b).

[Hydrolysis in acidic medium (corresponding to both artificial liquids)] L Test compound A and B'L vc method 1000wt A to 2-Of salt, 10To hydrochloric acid 24-,
The purified product was dissolved in an acidic medium (p#i, l) containing pepsin 121, shaken in 37C, and heated in a sun cylinder over time, using an instant liquid chromatography method using a continuous hole distribution column. The hydrolysis rate of each sample was determined from the magnitude of the peak.

λ k Table 2! ! As shown in Figure 2, A is definitely more stable than B in an acidic medium.

[Hydrolysis in basic medium (corresponding to artificial intestinal fluid)] L
Test compound Disodium phosphate 9M 3&8fS 10% in A and B 2 Test Method 1000-
The test compound was dissolved in a basic medium (p7/7.s) containing 2.8f of acid and createne, and the hydrolysis of each test compound was carried out in the same manner as in the case of the acidic medium described above. I'm in danger of finding a rate.

As shown in Table 3, it is less expensive than AIdB in a basic medium.

〔others〕

The results of using the toxicity of A (to L) on Mawas (4a age ddY yarn) are as follows.

Oral administration> oooda/Kf, intraperitoneal administration L430hi
/ 11 Intravenous administration 557■ / as above 4°
．． Although the 3-sooxole:/-2-,:-conductor is extremely useful as a modifier for pharmaceutical prodrugs, such usefulness cannot be predicted at all from conventional knowledge.

That is, 4-methyl-5-phenyl-1,3-sokylin-2-one and 4,5-dimethyl-1,3-sokylene-2-one, which are the starting materials of the present invention, are obtained from Liepiig's chemical compound. 1 Volume 764, 116~
124 pages (1972), Tetoshihedron Letters,
1972, pp. 1701-1704 and U.S. Tokken No. 290, for the 1.3-dioxolene-2-one derivative represented by the general formula (1'l), There is no record of the visit.Also,
Liebig's Annalen der Heshi-1977,
For 2 to 32 negative, 4,5-bis(bromomethyl)-1, which is an intermediate raw material for polymer production, is produced by brominating 4,5-dimethyl-1,3-dioxolen-2-one.
, 3-dioxolen-2-one can be obtained, but there is no specific description of the method for producing Kl, 3-dioxolen-2-one derivatives, and there is no suggestion regarding its use. .

The method for producing the 1,3-dioxolen-2-one I% conductor of the present invention involves adding a compound represented by the general formula [where R1 and R are the same as 1] above at room temperature or generally under heating conditions. This is achieved by reacting preferably 0.8 to 1.2 moles of hydrogen under radical generating conditions.

Compounds of the general formula [seal] with starting materials, e.g. Harry Bitzhs Annalen Der <-1g 764 volumes, 11
pp. 6-124 ($19?21), Tetrahet Buyer Letters, 1972, 1701-l? Page 04, and US Patent 11i & 0! It can be synthesized according to the known method disclosed in A$+ No. 90 and the like.

Examples of the halodating agent include chlorine, bromine, N-bromophthalimide, N-bromosuccinimide, N-chlorophthalimide, and N-chlorosuccinimide. In order to proceed with the reaction between the raw material represented by the general formula [door] and the halodanizing agent, ultraviolet rays are irradiated during the reaction, or α,α'-azobisisobutyronitrile, benzoyl peroxide is added to the reaction solution. It is preferable to use a radicalizing agent such as.

An appropriate reaction solvent is selected depending on the properties of the raw materials, such as methylene chloride, chloroform, carbon tetrachloride,
Examples include ethylene tetrachloride and benzene.

Also, general formula [! ] in which X is an iodine atom %j
can be obtained by reacting a compound of general formula [1] in which X is a bromine atom or a chlorine atom with sodium iodide or potassium iodide according to a conventional method.

The present invention will be specifically explained below by giving examples and reference examples.

Production of 4-bromomethyl-5-phenyl-1,3-dioxolene-2-one; 4-methyl-5-phenyl-1,3-dioxolene-2
-one (synthesized according to Liebig's Annalen der Hemi-1 Vol. 764, pp. 116-124, 1972) 2.4f (ao13@mole) was dissolved in carbon tetrachloride 15 (
Id was bath-dissolved, and 2.9f (1 g of ao, 2 moles) of N was added to it.
- Bromosuccinimide A catalytic amount of α,α'-azobisisobutyronitrile was added and heated under reflux for 90 minutes. The reaction solution was concentrated to half a ton, the insoluble matter was separated, the P solution was condensed, and the residue was recrystallized from a mixture of benzene and cyclohexane to produce colorless needle-like crystals, melting point 9α5~st, sc purpose @ 2.3
? (yield: 66%).

Elemental analysis, molecular formula C, @H, Bf″O1: Theory m (%)
C, 47, 09: #, 2.77: Br3133° Experimental value (%) Ct47y! ! :B, 5L64:By.

31.29゜IR (KBr, yca-”)
: Around 1825 (Carl〆nil). NMR (CCj,)
J (ppm) Htas (-C:H, By, a), 7.
40 (He 7 se 7 break.

a) Example 2 4-bromomethyl-5-methyl-1,3-dio Φsure 7
-2-one production: 4,5-dimethyl-1,3-dioxolen-2-one (
Tetrahedron Letters, 19724E, 1701-
142t (α03 mol) synthesized according to 1704
was dissolved in 150 m of carbon tetrachloride, and 5.34 f
(a 03 mol) (DN-)o% succinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added, and the mixture was heated under reflux for 15 minutes.

After reducing the reaction solution to half a ton and removing the waste material, 14 L of P solution remained. The cilantro-like residue was distilled under reduced pressure to obtain the desired product 4.2f (yield 73%) as a colorless liquid with a boiling point of 115 to 120 C/5 UI Hg.

Elemental analysis, molecular formula C@H@BrOs = theoretical value (%):
C,31,111:#,! 61: Br, 41.40° Actual Mfl (%): C, 31,30#, 149 By.

41.31. I7i: (=-t, ν(+11-"
): around 1825 (carganyl) NMR (CCI,) δ (pp): λ1O (-CB,,
a), 4,1 O(-CM!Br, a) Example 3 Preparation of 4-bromomethyl-1,3-dioxolen-2-one: 4-Methyl-1,3-diokyln-2-one (U.S. Pat. 3020.290)&6t(α0
86 mol) was dissolved in 200 m of carbon tetrachloride, and 17
．． 8F (0.01 mol) of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added and heated to reflux for 90 minutes. The following treatment was carried out in the same manner as in Example 2 to obtain a colorless liquid with a boiling point of 94 tons. /3■H7) target product 5.2f (yield 316%) was obtained.

Element digit, molecular formula C, H3BrO,: Buried value (%) 2C
, 2 & 84: #, 119: By, 44g! , experimental value (%
) :c, 26.94, fi, Lu1l :B
r.

4460° IR, C11-''): around 1830 (carnyl) NMR (CCJ4) δ (ppm): 410 (-C
H, B.T.

1),? , G O (= CM-0-, a ) Example 4 Preparation of 3-bromo 1,2-calyldioxycyclohexene: 1,2-carbonyldioxycyclohexene (Tetrahedron Letters, 1972, 1701- 1704j
synthesized according to j) 2.15? (0,015 mol) was dissolved in 80-carbon tetrachloride, and 2.3f (α013
moles) of N-bromosuccinimide and catalytic amounts of α, α
'-Azobisisobutyronitrile γ was added and heated under reflux for 20 minutes. The reaction solution was cooled and filtered, and the F solution was swabbed with a low melting point to obtain the desired crude product, 2V (light brown liquid). JR (nee m), L3-40 (*-like hydrogen, m) Since the crude product of this target product is unstable, it was reacted with ampicillin without making a single oyster to obtain ampicillin ester (reference? See l11@).

(Reference Example 1) Ampicillin trihydrate was dispersed in 500jVt-dimethylformamide 6-, and potassium salt carbonate 125W1 was added to it.
υ■, cooled to OC, and added 0.0 g of int aldehyde.
7 liters of 25- were added and stirred for 25 hours under OC.

Next, potassium electrocarbonate 125M9 and 3-bromo 1゜2-
Cal is nyldioxycyclohexene 250■ (Example 4
Samurai (crude product) was added thereto, and the mixture was further stirred for 3 hours at oC. After the reaction was completed, the reaction solution was poured into ice water, the precipitated solid was extracted with ethyl acetate, and the organic layer was extracted with water. ! 〇- and 3
After washing twice and replacing with anhydrous madanesium sulfate, ethyl acetate was distilled off under reduced pressure to obtain a yellow slag.

The slag-like residue obtained as above was dissolved in acetonitrile with 4sdKil, adjusted to pH 16 with diluted hydrochloric acid, and heated at oC for 3 hours.
After stirring for 0 minutes, 10 mg of water was added and the acetonitrile was distilled off under reduced pressure. The aqueous layer was washed repeatedly with ethyl acetate, and then the salt was saturated. The precipitated oily substance was extracted with methylene chloride se-, and saturated brine Washed with. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated to the latter half of t, and inzolopyl alcohol 3.- was added and concentrated again under reduced pressure to obtain a pale yellow solid.

This solid was washed with inzolopyl alcohol and ether, and then ampicillin (2,3-cal dirusoxy-2
256 ml of colorless amorphous solid of -7 chlorohethycenyl) ester hydrochloride was obtained. Melting point 140C (decomposed). IR(KEr
, Mca-”):1830.1780,1750
(Force A/znil).

169G (amide) When the above ampicillin ester hydrochloride was incubated in 40% mouse blood at 37C for 10 minutes and then subjected to bioautography, it was found that all of the ester was converted to ampicillin.

(Reference Example 2) Ampicillin trihydrate and 4-
Ampicillin (5-)uni-2-oxo-1,3-nooxolen-4-yl) methyl ester hydrochloride was obtained from bromomethyl-5-phenyl-1,3-1/oxolen-2-one.

Yield 46-4%, colorless amorphous solid, melting point 1401:"
decomposition), IR (KBr, vx-”): 1830°1
785.17SO (Carbonyl Ltgs.

(amide) This ampicillin (S-hue, nyl-2-oxo-1,
After incubating 3-dioxolen-4-yl) methyl ester hydrochloride in 40% mouse blood for 5 minutes, bioautography was performed and it was found that all of the ester was converted to ampicillin. .

(Reference f13) Ampicillin trihydrate and 4-
Bromomethyl-bromo-methyl-1,8-dioxolea 2
-one to ampicillin (i-methyl-2-oxo-1
, S-8/oxolen-4-yl) methyl ester hydrochloride was obtained.

Yield 5α6%, colorless amorphous solid.

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

IR (KBr, Vex-”): 1g25.178
5.

1750 (carganyl), 1690 (amide) This ampicillin (5-methyl-2-oxo-1,3-f/oxolen-4-yl) methyl ester hydrochloride was added to 40% mouse blood for 5 minutes at 3°C. After incubation, bioautography was performed and it was found that all of the ester had been converted to ampicillin.

Claims (5)

[Claims] (1) It is represented by the general formula (in the formula, R1 represents a hydrogen atom, a lower alkyl group, or an aryl group, L is a hydrogen atom, or R1 is cyclically bonded to R1 through a chain). 1% (In the formula, X represents a heron atom, and R, R, and l are the same as above.) Method of manufacturing On-visit monuments. (2) %l in which the halodanizing agent is a chlorinating agent or a brominating agent
F'Flli1i The manufacturing method according to item 1. (3) Patented IR# ice range first panicle or sweetfish second term IC-listed whale foot method in which the reaction is carried out in an aprotic inert organic solvent. (4) Special rust-seeking model using graded hydrogen or halodanized hydrocarbon as the aprotic inert organic solvent! 28. The manufacturing method according to paragraph 3. (5) The production method according to any one of claims 1 to 4, in which the reaction is carried out in the presence of a radical fat-inducing agent or under ultraviolet irradiation.