JPS6048996A - 5-(e)-(2-bromvinyl)-2'-desoxyuridine and derivative manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention The present invention is based on the general formula (lA) R (where R is a hydrogen atom, an alkanoyl group having a chain length of 1 to 8 carbon atoms, an unsubstituted or 5-(B)-, which means an alkyl group of 4 carbon atoms or a benzoyl group substituted with a halogen atom.
The present invention relates to a method for producing (2-bromvinyl)-2'-desoxyuridine and its derivatives. The present invention is useful in the pharmaceutical field.

The preparation of 5-(F;)-(2~bromvinyl)-2'-desoxyuridine (VI, R=H) is known in the literature (5
). This compound is the best anti-inflammatory agent to date and a non-toxic chemotherapeutic agent with the highest efficacy and best selectivity against Herpes 81mplec I virus and Varicella Zoster in vitro and in vivo. (E, DeO'1ercq et al.
Free.

Natl, Acaa, 8ci, USA 76, 29
47/1979/; P, O0Mandga'l et al.
Graefea Arch, Ophthal-mol
, 216°261 /1981 /; E, De
Olercq et al., Brltisch Med.

J, 2B1.1178/1980/).

One method is the condensation: 5-(E)-(2-bromvinyl)-t-rasyl is bis-〇-) as a limethylsilyl derivative, 1-chloro-2-anxy-3Z5/
-di0-p-) is condensed with α-ri-erythrobentafuranose. (A.

S,,rones,R,T,Wag-ker,P
, 1. Barr and E.

DeOlercq, O82915254).

The disadvantage of this method is the complicated synthesis and low yield of the starting material 5-bromvinyl-uracil.

The product (Vl), in isolation, contains a mixture of α and β anomers, of which only the β form is of practical importance (6). 5-Bromvinyl-uracil is made by converting 5-7 cetyl-uracil to 5-vinyl-uracil. 5
Calculated from -acetyl-uracil, compound ■ (R=H
) yields are less than 10% and, moreover, chromatographic resolution of α and β isomers is required (A, S, Jo
nes, G.

``li'erhelst and R.T. Walker.
Tetraheclron Letters 45.4
415/1976/). Currently, 5- (Fi)-(2
-7'romvinyl)-uracil is made in high yield from 5-formyl-uracil via 5-(I)-(2-carboxyvinyl)-uracil. Condensation by the above method naturally produces an anomer (α:β=11) even if the protected, activated, and functionalized sugar derivative used in the condensation contains chlorine at the 1-α position ( P.J.
Barr.

A., S. Jones, G. Verhelst and R.
-T, Walker.

J., Ohem, Sac, Perkin, T.
1665/1981/).

Berthaström method (D, E, Bergström: m
and M.

K, Ogawa, JAO8100,8106/197
8/') and its variations (A, S, Jones,
G, Verhelst and RoT.

(7) Wa'1ker, Tetrahedron Lette
rs, 45, 4415/1979/) is preferred as the condensation method. 2'-desoxyuridine to c-5-mercury-
2'-desoxyuridine), which was converted into L12Pd01
4 and ethyl acrylate! Ri 5- (Fi)
-(carboethoxyvinyl)-2'-desoxyuridine, from which compound M (R=H) is obtained by hydrolysis. Since β-2'-desoxyuridine is used as the starting material, no anomeric mixture is formed.

The disadvantage of this method is that LiPd0A! 4 and 2'-denxyuridine are extremely expensive, and the final product must be purified by column chromatography, making the production costly and complicated.

5-(E)-(2-bromvinyl)-2'-desoxyuridine (formula ■, R=H) is also made from 5-ethyl-21-desoxyuridine by bromination (D,
BarWC+1ff and P, Langen, Nuq
leicAcids, Res, 5pec, Pub
1, 29-51/1975/). In this process, the beta anomer of 5-ethyl-2'-desoxy(8)uridine is converted to 3',5'-di-0-acetyl-5-ethyl-21-denxyuridine, which is then converted to bromine by elemental bromine. followed by dehydrohalogenation with a tertiary base.

Finally, after deacetylation, the final product (R=H) is formed.

The disadvantage of this method is that the β anomer of 5-ethyl-21-denoxyuridine used as a starting material is
This has to be obtained by resolution of the anomeric mixture. Furthermore, in this process anomerization can take place during the bromination, in which pure β-diacyl compounds (■
) gives rise to a mixture of α- and β-bromine compounds in a 1:1 ratio.

The aim of the present invention is to create a new method for the preparation of compound (1) using different starting materials.

In the present invention, R in the general formula (1) in the following reaction formula has the above-mentioned meaning. ) was found to be an economically preferred starting material.

(9) 5-(E)-(2-bromvinyl)- indicated by 2■
The method for producing 2'-desoxyuridine and its derivatives according to the present invention comprises 3/, 5/-di-0-acyl-5 of the general formula W.
- Ethyl-21-denxyuridine is reacted with elemental bromine and the resulting dibrome derivative of the general formula V, in which R has the meaning given above, is optionally desorbed after isolation. It is characterized by hydrogen halogenation followed by optional deacylation.

00) l　M y　Vi R ■　■(β:α=:65:35) (11) In a preferred embodiment of this method, 3'.

5'-di0-acyl-5-ethyl-2'-desoxyuridine (transformation) Preferably, 1 mole of α,β anomer mixture of sf-p-chlorobenzoyl derivative is reacted with a halogenated hydrocarbon, preferably dichloromethane, Dissolve in chloroform, dichloroethane, tetrachloromethane or a mixture thereof and react with 2-3 mol of bromine under the action of light. The resulting dibrome compound of general formula V is subsequently dehydrohalogenated with an excess of a tertiary base, such as triethylamine, either directly in the reaction solution or after isolation and redissolution in a halogenated hydrocarbon, preferably dichloroethane. and optionally finally remove the acyl group with a short-chain alkanol and an alkali metal alcoholade.

The resulting compound (1) can be used in pharmaceutical preparations. Compound M (R: H or R-metabolically separable acyl group)
in pure form and with other active substances and/or binders,
It is used in combination with solvents, diluents, flavoring agents and/or other auxiliaries.

The compounds are formed into solutions, emulsions, suspensions, powders and pastes in a manner known per se.

The use of this compound in medicine is virtually free of side effects.

The novel compound made according to the present invention has the formula ■: R: 0O
OH, and R=p-chlorobenzoyl. These are also objects of the present invention.

The di-0-acyl protected starting compound (1) is well brominated, its synthesis is simple, and furthermore, deacylation and reacylation of the ethyl compound is not required. A further great advantage of the process according to the invention is that α,β anomer mixtures can be used for the bromination. This method therefore results in significantly higher yields. That is, under the conditions of dehydrobromination, most of the beta form of compound (1) is precipitated with triethylamine hydrogen bromide, and only a large portion of the beta anomer remains in solution together with the alpha anomer. Compound ■ (pure β
Starting from form), the yield of compound ① is 22.5%, while starting from θ3) α,β mixture, 35.7% is obtained (calculated from sugar compound ①).

The present invention will be further explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 1-1 Starting 'lE quality p-chlorbenshii/l/-5
-ethyl-2'-desoxyuridine (β anomer and α
, β anomer) (a) 2.4-bis-trimethylsilyl-5-ethyl-pyrimidine (1) 5-ethyluracil (I
) of 1009 (0.71 mol), 200d (1,2 mol)
5 mol) of 1,1,1,3,3,3-hexamethyldisilazane (EMDS) under reflux for 24 hours under anhydrous conditions.

From the resulting clear solution, excess HMDS is distilled off at normal pressure and the residue is fractionated under reduced pressure.

Boiling point = 134°C/1735Pa, yield: 197.4&(
97%) (b) 2'-Detxy31.51-di0-p-chloro04) Rubenzoyl-α,β-ribo7lanooxyl chloride 10g of 2'-de/xyD-ribose to 190-anhydrous Dissolve in methanol, then add 10 ml of anhydrous methanol containing 1% hydrogen chloride, and after 20 minutes,
Add 20035g. The mixture is filtered through filter paper and the liquid is rotary evaporated at 40°C. The vapors are collected with 5 ml of anhydrous pyridine. The residue (syrup) is dissolved in 58° of anhydrous pyridine and, under water cooling, 22.5° of p-chlorobenzoyl chloride is added such that the temperature remains between 20°C and 40°C.

The flask is closed with OaO tube and left at room temperature for 16 hours. After addition of 50 ml of water, the solution was extracted twice with 75 ml of dichloromethane through a separatory funnel, and the extract was extracted twice with 10 ml of dichloromethane.
Wash with ml of 10% KH (303 aqueous solution) and Na2
Dry with EI04. After evaporation of the solvent, the residue is dissolved in 75% anhydrous ether and the solution is cooled to 0° C. (15). After adding 200 ml of glacial acetic anhydride saturated with hydrochloric acid, dry hydrochloric acid gas is introduced until precipitation of a white product has ended. The product is quickly separated from F, washed with ice-cold ether and dried with P2O5 and KOH in a vacuum dessicator. The product is purified without recrystallization.

Melting point 118 °C, yield 24 I (75%) product 1:1
(thin layer chromatography,
Silica gel HF254 (Merck AG type 60
), vehicle system = chloroform/ether (7:l).

(c) 5',5'-di0-p-chlorobenshiyl-5-ethyl-2'-desoxyuridine 88.5
9 (0.51 mol) of 2,4-bis-trimethylsilyl-5-ethyl-pyrimidine (1) was dissolved in 39001d anhydrous acetonitrile, and 3009 molecular sieves (Merck 4A) were immediately added to the solution.
04.6 g (0,243 mol) of 2'-Dexys
l, 51(16) - C 0- p-Chlorbenshiyl α, β-D-ribofuranosyl chloride (m) and 41.8 g of dry H
Add fBr2. After 2-3 minutes under stirring, the solution becomes clear and crystals begin to separate.6 The mixture is stirred slowly for 5 hours and left overnight at room temperature. 31,5
The pure β anomer of 1-di0-p-chlorobencyyl-4-〇-trimethylsilyl-5-ethyl-2'-desoxyuridine crystallizes out.

(c/I) Isolation of β Compound (P/) This sludge is filtered and the P solution contains a mixture of α and β. ), and washed three times with 150 g of chloroform. The molecular sieve remains as a residue on the filter. - Shake the combined chloroform solution with 50 ml of the 30% solution in a separatory funnel. The chloroform phase is dried ``04''t', filtered and evaporated under reduced pressure.

Dilute the residue with 96% ethanol 4 J and K 2 (17) Boil for an hour. Pure at room temperature after cooling β-form■ compound of is precipitated and ethanol recrystallize from

Melting point 196-197 °C, yield 42.5 g (52.6%: calculated from compound ■) (c/I) Isolation of α, β anomer mixture ■ After condensation, the reaction mixture as an acetonitrile solution was brought to room temperature for 12 After a period of time and filtration, the sludge is dissolved in 150-chloroform. Wash the remaining tamolecular sieves three times with 150-ml chloroform (the β form y dissolves).

Evaporate acetonitrile F solution (α, β anomer solution),
Add 1 part of chloroform to the residue. A precipitate forms and is washed away. Then, the combined chloroform solution was shaken with 150 ml of 30% solution in a separatory funnel, the chloroform phase was separated, dried with MfSO4 (1B), and filtered. The solvent is then distilled off and the residue is heated under reflux with 6 portions of 96% ethanol for 50 minutes. After cooling to room temperature, the α,β-form product Qv) precipitates out.

Yield: 96. ! 9 (total ratio 73.8%) Isomer ratio β:α = 3:1 1.2 5- (E) -(2
-promvinyl) -27-desoxyuridine (■, R
: Production of H)26.69 (0.05 mol) of 3',5'-G〇-
p-Rubenzoyl-5-ethyl-2'-desoxyuridine (α,β anomer mixture, β:α==3:1
) is dissolved in 350 mL of hot anhydrous dichloroethane and then 6.8 d (0,125 mol) of bromine in 60 ml of anhydrous dichloroethane are added dropwise in a stream of dry nitrogen under the action of light, depending on the reaction rate. (about 20-25 minutes). After the addition of bromine, the light irradiation is stopped and the reaction mixture is boiled for a further 15 minutes under reflux with a generous nitrogen purge. The solvent is then rotated (19) and evaporated again using 20 ml of anhydrous dichloroethane. The residue (hard foam) was then dissolved in 140 ml of anhydrous dichloroethane and 10.4 mL (0,075
mol) of triethylamine dropwise (over about 15 minutes).

The compound β form Vi (R=p-chlorobenzoyl) and triethylammonium hydrogen bromide precipitate out of the solution and are washed with dichloroethane and subsequently with 80% ethanol after filtration.

The residual liquid is pure β form V ((R=p-chlorobenzoyl).

Yield 14.8 g (0,024 mol = 48%) Deacetylation is carried out as follows: 221.09 (0,0545
M(R=p-chlorobenzoyl) of 150 d
(0,5 mol) deacetylated with NaO0i(s solution for 73 hours at room temperature under stirring. Dowsx 5
Adjust the pH of the solution to 5-6 with 0H+ ion exchange material. The ion exchange material is separated from the furnace and washed with methanol-vf.

- Combined methanol fraction (20) Evaporate and recrystallize the residue from water.

Melting point 175-176°C, yield 7.49 Vi (R=H) ('92.6%) Example 2 5-(E)-(2-brombini) from pure β form
v) Preparation of -2'-desoxyuridine (■, R=H) Pure β anomer 3/,5/-di0-p-chlorobencyyl-5-ethyl-2'-tesoxyuridine (βN
) 26.79 (o, o s mol) was dissolved in 350 ml of hot anhydrous dichloroethane and heated to 60 ml under light and a stream of nitrogen.
6.8rd in m1 of anhydrous dichloroethane, (209:
0.125 mol) of bromine are added dropwise (20-25 minutes) depending on the reaction rate. After the addition of bromine, the irradiation is stopped and the reaction mixture is boiled under reflux for 15 minutes under a strong nitrogen purge. The solvent containing the remaining HBr is rotovaped. 20
Carry out vaporization again using pure anhydrous dichloroethane.

The pale yellow residue was dissolved in 140 m of anhydrous dichloromethane (21) and dissolved in 10.4@9 (7,599,20,07
5 mol) of triethylamine (approximately 15 minutes)
. Compound β form ■ (R=p-chlorobenzoyl) from solution
and triethylammonium hydrogen bromide precipitate out, which is filtered and the F residue is washed with dichloroethane and then with 80% ethanol (in which the hydrogen bromide is dissolved). Residue (
Compound ■, 21°Og = = 0.0345 mol = 69%)
is deacylated with 130 ml (o, 5 mol) of Na0OHs at room temperature for 3 hours. Adjust the solution size to 5-6 using DoWθx50H+ ion exchange material. Separate the ion exchange material and wash it twice with methanol. - Rotary evaporate the combined methanol fractions and recrystallize the residue from water.

Melting point 175-176℃, yield 10.61! (■, R==H) (65.7% calculated from starting material ■, M(R==p-
(22) Starting from compound ■ (R=I)-10 rubenzoyl) (pure β form), the yield of compound ■ is 22.5%, while ,α
, a yield of 35.7% is achieved (relative to sugar compound ■) starting from the β mixture.

Example 6 1.079 (2 mmol) of 5-ethyl-(sl, sl
-di-p-chlorobenzoyl)-2'-tesoxyuridine is dissolved in 25 ml of anhydrous chloroform and 0.11 m of bromine in 5 ml of chloroform is added dropwise under 500 W light irradiation. The resulting HBr is blown away with N2. After addition of bromine, add 0.6 ml of triethylamine and heat for a further 10 minutes. The solvent is rotary evaporated, the triethylammonium bromide is optionally removed beforehand by extraction with water, and the residue is recrystallized from ethanol.

Yield 0.89 = 66% of 5-(2-bromvinyl) −
s', 51-di-p-chlorobenzoyl)-2'-β-
Desoxyuridine.

Melting point 235℃ (23) The protecting group is removed by methanolysis.

Yield 0.4g - 60% of theory, melting point 170°C Example
4 340 d (1 mmol) of β-3',5'-diacetyl-5-ethyl-2'-desoxyuridine was dissolved in 100 ml of Co/4 under reflux and under the action of light (light lamp 25
0W) and add 350+II9 bromine over 1-2 hours. The solvent is then removed under reduced pressure and the residue is dissolved in 20 g of diisopropylethylamine. This was heated under reflux for 15 minutes.
boil for minutes and then isolate s-(Fi)-(2-bromvinyl)-(sl, 51-diacetyl)-2'-β-desoxyuridine (melting point 164°C, needles from alcohol) or immediately The acetyl group is separated from the reaction solution with 50 ml of ammonia-saturated methanol.

After removal of the solvent, the residue is purified by chromatography.

Yield 206■ = 62% of 5-(2-bromvinyl)-2
'-Desoxyuridine, melting point 162-163°C (24) Example 5 A solution of 5.49 (10 mmol) of x,f,5L-diacetyl-5-ethyl-2'-denxyuridine in 600 ml of carbon tetrachloride 1.1 ml of bromine are bubbled in with dry nitrogen under reflux, stirring and light irradiation. Next 1
Add 0 ml of triethylamine and heat for a further 15 minutes. The solution is filtered, rotovaped, deacetylated with 100 ml of ammonia-saturated methanol and eluted with chloroform/methanol(N) on silica gel (Merck).

Yield 1.3g, melting point 169℃ (25)

Claims (1)

[Claims] 1, 5- (E) -(2-bromvinyl)-2'-
Desoxyuridine and the general formula ■ R (where R is an alkanoyl group with a chain length of 1 to 8 carbon atoms, unsubstituted or substituted in the para position with an alkyl group of 144 carbon atoms or a hydrogen atom) (means a benzoyl group.) In the method for producing a derivative represented by the general formula (1) 3 represented by R: s/-di-0-acyl-5-ethyl-
2'-desoxyuridine is reacted with elemental bromine and the resulting dibrome derivative R of the general formula V is then dehydrohalogenated without or after isolation,
Furthermore, 5-(E)-(2-brombini#)-2'
- A method characterized by deacylation when producing desoxyuridine. Claim 1 in which a mixture of α and β anomers of 3', 5'-di(2)-0-p-chlorobensyyl-5-ethyl-2'-desoxyuridine is used as the diacyl derivative of general formula (2). Method described. 3. The bromination is carried out in a halogenated hydrocarbon under the action of light, and the resulting dibrome derivative is subsequently treated with an excess of tertiary base either directly in the reaction solution or after isolation and redissolution in the halogenated hydrocarbon. 3. The method according to claim 1 or 2, wherein the dehydrohalogenation and deacylation are carried out with. 4. The method according to claim 1, wherein R is 0OOH. 5. The method according to claim 1, wherein R is p-chlorobenzoyl. & General formula ■ Uba (3) (where R is a hydrogen atom, an alkanoyl group with a chain length of 1 to 8 carbon atoms, an unsubstituted or alkyl group of 1 to 4 carbon atoms in the para position, or a halogen means a benzoyl group substituted with an atom), in which the compound of formula (Vl) itself or with other active substances and/or binders, solvents, diluents, flavoring agents and/or mixed with other auxiliaries to form a medicine. 7. The method according to claim 6, wherein R is a metabolically separable acyl group. 8. 5-('')-(2(4) monobromvinyl)-2'-desoxyuridine derivative represented by the formula (Wl R (where R means 0OOH3 or p-chlorobenzoyl).