WO2001096326A1

WO2001096326A1 - Alpha-phenylsulphinyl-alpha-halogeno-butyrolactone and halogeno-2-buten-2-olide-4 compounds useful for preparing halogeno-2-oxymethyl-4-furanone(4h)

Info

Publication number: WO2001096326A1
Application number: PCT/FR2001/001884
Authority: WO
Inventors: Jean-Claude Caille; Anthony Mckervey; Paul Armstrong; Hugues Miel
Original assignee: Ppg-Sipsy (Sca)
Priority date: 2000-06-15
Filing date: 2001-06-15
Publication date: 2001-12-20
Also published as: FR2810319A1; AU2001269171A1

Abstract

The invention concerns compounds of formula (I) wherein: R is selected among a hydrogen atom, a C1-C6 alkyl group or aryl group optionally substituted; X represents a halogen such as a fluorine, bromine, chlorine or iodine atom; Y represents a -S(O)Ph group or a double bond between carbons 2 and 3, and in the latter case R is not a hydrogen atom and X is not a fluorine atom. The compounds of formula (I) are useful for preparing halogeno-2-oxymethyl-4-furanone-(4H) compounds which enable the synthesis of analogues of nucleosides constituting active agents in the treatment of viral infections.

Description

ALPHA-PHENYLSULFINYL-ALPHA-HALOGENO- BUTYROLACTONE AND HALOGENO-2-BUTEN-2-OLIDE-4 COMPOUNDS USEFUL FOR THE PREPARATION OF HALOGENO - 2 - OXYMETHYL - 4 - FURANONE COMPOUNDS (4H).

The present invention relates to new intermediates for the synthesis of halogeno-2-oxymethyl-4 - f uranone (4H) compounds. The invention relates more particularly to the preparation of halogeno-2-alkoxymethyl (or hydroxy or aryloxy) -4-uranone (4H) compound which are useful for the preparation of nucleoside analogs constituting active agents in the treatment of viral infections and especially by the HIV or HBV viruses.

The compounds of the invention correspond to the following formula (I):

Which can also be represented by the following two formulas:

In which R is chosen from a hydrogen atom, a C ₆ alkyl group or an optionally substituted aryl group,

X represents a halogen such as a fluorine, bromine, chlorine or iodine atom,

Y represents a group -S (0) Ph or a double bond between carbons 2 and 3, and in the latter case R is not a hydrogen atom and X is not a fluorine atom.

When R is a C ₁ _ ₆ alkyl group, this may be substituted by a C ₁ -C ₅ alkyl group advantageously from C _ ₅ or an aryl group, and when R is an aryl group, that may be substituted by an alkyl group in C ₁ _ _β advantageously in C ₁ _ ₅ . Thus, the invention more particularly contemplates the compounds of formula (I) in which R represents a triphenylmethyl, tert-butyl or benzyl group.

The compounds of formulas (I) above can be optically active or not.

The invention relates more particularly to two classes of compounds of formula (I) according to the meaning of Y.

A first class of compounds of formula (I) are the alpha-phenylsulfinyl-alpha-halogenobutyrolactone compounds, optically active or not, where Y represents a group -S (0) Ph. These compounds correspond to formula (II) below:

Which can also be represented by the following two formulas:

In which R and X have the same meaning as in formula (I).

A second class of compounds of formula (I) are the alkoxymethyl-4-halogeno-2-buten-2-olide- 4 compounds, optically active or not, where Y represents a double bond between carbons 2 and 3. These compounds respond to formula (III) below:

Which can also be represented by the following two formulas:

In which R and X have the same meaning as in formula (I). As indicated above, the compounds of formula (III) in which R is a hydrogen atom and X is a fluorine atom is not part of the invention.

The compounds of formulas (II) and (III) are intermediates for the synthesis of halogeno-2- alkoxymethyl (or hydroxy or aryloxy) -4-furanone (4H) compound of general formula (IV) below:

Which can also be represented by the following four formulas:

(IVa) (IVb) (IVc) (IVd)

In the sque lles R and X have the same meaning as in formula (I). Thus, the compounds of formulas (IV) can be prepared from the compounds of formulas (III), themselves obtained from the compounds of formulas (II). The invention therefore also relates to the processes for preparing the compounds of formulas (III) and (IV) respectively from the compounds of formulas (II) and (III) •

The compounds of formula (IV), optically active or not, are prepared from the compounds of formula (III) by a hydrogenation reaction in the presence of palladium on carbon.

The compounds of formula (III), optically active or not, are prepared from the compounds of formula (II) by a reaction for removing sulfur oxide advantageously carried out by heating in a solvent such as toluene.

The compounds of formula (III) can be obtained as described in the prior art (C.K. CHU, J. Med. Chem., 1999, 42 (7), p 1320).

The compounds of formula (II) can be obtained from phenylsulfinyl lactone compounds of formula (V) below by a halogenation reaction in the presence of a metal hydride and then of a halogenating agent:

Which can also be represented by the following two formulas:

In which R has the same meaning as in formula (I).

The compounds of formulas (V) are prepared from phenylthio-2 -alkoxy (or hydroxy or aryloxy) methyl -4-uranone (4H) compounds of formulas (VI) below by an oxidation reaction, advantageously in using methyltrioxorhenium (MTO) and hydrogen peroxide -urea (UHT) as an oxidizing agent:

Which can also be represented by the following two formulas:

In which R has the same meaning as in formula (I).

Finally, the compounds of formulas (VI) can be prepared from glycidol derivatives (alkyl or aryl e glyc i do l), optically ac t i f s or not, and commercially available, of formula (VII) below:

In which R has the same meaning as in formula (I).

The compounds of formula (VI) can be prepared by a condensation reaction of the compounds of formula (VII) with phenylthioacetic acid followed by a cyclization reaction of the product obtained by heating a toluene solution of said product under reflux.

The invention therefore also relates to all or part of the reaction scheme leading to the compounds of formula (IV), (III) or (II) from the compounds of formulas (VII) according to the reactions described above.

A further subject of the invention is therefore the use of the compounds of formulas (II) for the preparation of the compounds of formulas (III) or (IV) optically active or not, as well as the use of the compounds of formula (III) for the preparation of the compounds of formula (IV) optically active or not. Other advantages and characteristics of the invention will appear from the following examples, given without limitation, concerning the preparation of the compounds of formulas (II), (III) and (IV).

Example 1: Preparation of Fluoro-2-phenylsulfinyl-2-trityloxymethyl-4-dihydro-furanone- (4S) of formula (II) in which R is Triphenyl ethyl and X is fluorine.

1) Preparation of Phenylsulf anyl-2- trityloxymethyl-4 -dihydro-furanone- (4S) of formula (VI).

Mixture of the two diastereoisomers, then condensation of the (R) -tritylglycidol of formula (VII) with phenylthioacetic acid.

256.2 ml of LDA in solution in hexane (1.5 M, 0.384) are added to a 1 liter three-necked flask, closed by a septum and under a vacuum of nitrogen. mol, 2.7 eq) and 50 ml of anhydrous THF. The solution is cooled using an ice bath and then using a syringe, a solution of phenylthioacetic acid (26.9 g, 0.16 ml, 1.12 eq.) In 50 ml is added in portions over 15 min. anhydrous THF. When the addition is complete, the reaction medium is stirred for 1 h at a temperature below 5 ° C. A solution of (R) - tritylglycidol (45.1 g, 0.142 mol) in 100 ml anhydrous THF (100 ml) is added via a cannula. The ice bath is removed. The clear, cloudy yellow solution is stirred at room temperature for 18 hours. It is then poured into a separatory funnel containing a solution. hydrochloric acid (59 ml of concentrated HCl in 2 l of water).

Extracted with toluene (1 time 1 liter and 1 time 700 cc). The organic phases are combined and washed with 800 ml of water, with 800 ml of Saumur, then they are dried over MgSO ₄ and filtered.

The organic solution is concentrated to 4/5 of its initial volume, then it is brought to reflux for 2 h (1/2 h to reach the reflux temperature) by eliminating the azeotrope formed using a Dean- Starck (amount of water formed: 2, 15-2, 20 ml, Maximum expected: 2.55 ml). The medium is then cooled, then poured into a 2 1 separatory funnel.

The solution is washed with a saturated NaHCO ₃ solution (500 ml), with water (500 ml) and finally with Saumur (500 ml). The solution is dried over MgSO ₄ , filtered and concentrated in vacuo.

To the orange and viscous solid obtained, ether is added.

A white precipitate is quickly formed by grinding with a spatula. The resulting solution is stirred for 30 min at room temperature. It is then filtered and washed twice with a minimum of ether. The white solid obtained is dried at 40 ° C under vacuum (weight: 23.6 g, 35.6% of theoretical weight, purity:> 98% (HPLC)).

The filtrate is concentrated under vacuum, taken up in CH ₂ C1 ₂ and filtered through a frit (diam: 10 cm, h: 5 cm).

By washing the frit with CH ₂ C1 ₂ and concentrating under vacuum, an orange oil is obtained (weight: 32 g, an HPLC analysis indicates that this oil contains approximately 70% of lactone: 22 g, 33.33%).

A second portion (3.5 g, 5.3% of theoretical weight) of the lactone can be precipitated by adding ether to the oil. This precipitate is filtered and washed twice with a minimum amount of ether. A third fraction (4 g, 6% of theoretical weight) is obtained in the same way after 3 days.

A mixture of diastereoisomers, the majority of which (5S), is obtained, with a total yield of 47%

¹ H NMR (500 MHz, CDC1 ₃ ): The majority diastereoisomer: δ 2.05 (ddd, J = 8.96, 10.30 and 13.36 Hz, 1H, H _4a ); 2.57 (ddd, J = 6.64, 9.31 and 13.36 Hz, 1H, H _4b ); 3.16 (dd, J = 4.49 and 10.5 Hz, 1H, H _{1> a} ); 3.19 (dd, J = 5.3 and 10.5 Hz, 1H, H _1fb ); 3.93 (dd, J = 8.22 and 10.27 Hz, 1H, H ₃ ); 4.49 (m, 1H, H ₅ ); 7.2-7.5 (m, 15H, H _ar ).

^X NMR H (500 MHz, CDCl _3): Minority diastereomer: δ 2.23 (ddd, J = 6.87, 7.89 and 13.53 Hz, 1H, H _4a); 2.47 (ddd, J = 5.16, 9.17 and 13.53 Hz, 1H, H _4b ); 3.06 (dd, J = 3.63 and 10.6 Hz, 1H, H _x , _a ); 3.19 (dd, J = 3.16 and 10.6 Hz, 1H, H _1b ); 4.13 (dd, J = 6.86 and 9.17 Hz, 1H, H ₃ ); 4.49 (m, 1H, H ₅ ); 7.2-7.5 (m, 15H, H _ar ).

¹³ C NMR (125 MHz, CDCl ₃ ): Mixture of diastereoisomers. δ 31.9; 32.1; 45.0; 45.6; 64.80; 64.83 77.1; 86.8; 87.2; 127.1; 127.2; 127.91; 127.99 128.3; 128.4; 128.5; 128.6; 129.1; 129.2; 133.12 133.17; 143.2; 143.4; 174.4; 175.1.

2) Preparation of Phenylsulf inyl-2-trityloxymethyl-4-dihydro-furanone- (4S) of formula (V).

Mixing of the diastereoisimers then oxidation of the phenylsulfanyl compound.

19 g (0.0407 mol) of compound of formula (Via) (α-phenylthio-γ-butyrolactone), 3.91 g (0.0415 mol) of the peroxide complex are added to a 250 ml flask. hydrogen-urea (UHP) and 0.1 g (0.4 mmol) of methyltrioxorhenium (MTO). The reaction medium is stirred at room temperature and followed by a TLC analysis (Hexane / AcOEt: 70/30). A sample of the reaction medium is also analyzed by ^X H NMR after h30. There is some trace of product. Another 0.2 g (0.8 mmol) portion of MTO is added and the resulting solution is stirred at room temperature for 22 h 30. TLC and ¹ H NMR analyzes of a sample of the reaction medium indicate the complete consumption of the starting material. The reaction medium is filtered. The white precipitate is washed with 50 ml of dichloromethane. The CH ₂ C1 ₂ phase is concentrated under vacuum. 19 g of white solid are obtained.

Yid: 100%

^X NMR H (500 MHz, CDCl _3): Mixture of diastereoisomers. Only the main three. δ 1.58 (m, 1H, H ₄ ); 1.72 (m, 1H, H ₄ ); 1.95 (m,

1H, H ₄ ); 2.33 (m, 1H, H ₄ ); 2.55 (m, 1H, H ₄ ); 2.70 (m, 1H,

H ₄ ); 2.85 (dd, J = 3.48 and 10.67 Hz, 1H, E _1. ); 2.93 (dd,

J = 2.94 and 10.85 Hz, 1H, H _x ,); 3.17 (dd, J = 3.71 and 10.67

Hz, 1H, Hi.); 3.26 (dd, J = 3.1, 1 and 10.67 Hz, 1H, H _x ,); 3.30

(dd, J = 6.3 and 10.67 Hz, 1H, H _x ,); 3.69 (dd, J = 9.73 and 10.2

Hz, H ₃ ); 3.88 (dd, J = 8.57 and 9.6 Hz, H ₃ ); 4.28 (dd,

J = 8.19 and 10.4 Hz, 1H, H ₃ ); 4.4-4.5 (m, 2H, 2H ₃ ); 4.58

(m, 1H, H ₃ ); 7.1-7.6 (m, 60H, H _ar ).

3) Preparation of Fluoro-2-phenylsulfinyl-2-trityloxymethyl-4-dihydro-furanone- (4S) of formula (II).

5.5 g (12.4 mmol) of sodium hydride (60% mineral oil) are added to a three-necked flask closed with a septum and under a nitrogen vacuum, followed by 20 ml of anhydrous THF. This suspension is cooled to 0 ° C. A solution of 4 g (8.2 mmol) of the compound of formula (V), - phenylsulfinyl-γ-trityloxymethyl-γ-butyrolactone, in 40 ml of anhydrous THF is then added via a syringe in 10 min. The reaction medium is stirred at 0 ° C for 1 hour and then at room temperature for 30 min. The color changed during this time from bright yellow to orange then yellow. The medium is then transferred in 10 minutes and in portions via a cannula to a cooled solution of 2.84 g (8.7 mmol) of Selecfluor in anhydrous DMF. When the addition is complete, the medium is stirred at room temperature for 3 hours.

It is then poured into a 500 ml separating funnel containing an aqueous solution saturated with NH ₄ C1.0n, extracting the medium with 2 times 150 ml of ether. The ethereal phases are combined, washed with water (6 times 150 ml), dried over magnesium sulfate, filtered and concentrated in vacuo.

3.8 g of compound (I) are obtained (R is triphenylmethyl, X is fluorine and Y is -S (O) Ph).

Yield> 70%.

^X NMR H (500 MHz, CDC1 _3): δ 2.5-2.8 (m, 2H, H _4); 3.3-3.4 (m, 2H, H _{1 #} ); 4.68 (m, 1H, H ₅ ); 7.2-7.8 (m, 20H, H _ar ).

Example 2: Preparation of Fluoro-2-trityloxymethyl-4-buten-2-olide-4- (4S) of formula (III) in which R is triphenylmethyl.

To a 100 ml flask are added 3.8 g (7.6 mmol) of α-phenylsulfinyl- -fluoro-γ-trityloxymethyl-γ- butyrolactone of formula (II), 50 ml of toluene and 2 g of NaHC0 ₃ . The medium is brought to reflux for 9 min using a preheated oil bath. After cooling, the medium is filtered and concentrated under vacuum. 3.8 g of light brown solid are obtained.

About 10 ml of methanol are added and the solution is stirred for 15 min at room temperature. A white precipitate forms. The solid is filtered and washed with a minimum quantity of methanol. 1.8 g of white powder are obtained. The product is purified by column chromatography.

Melting point: 175 ° C [α] _D : -74.4 (0.99, CHC1 ₃ )

NMR ^ (500 MHz, CDC1 ₃ ): δ 3.40 (m, 2H, CH ₂ ); 4.95 (m, 1H, H ₄ ); 6.56 (t, J = 2.1 Hz, 1H, H ₃ ); 7.2-7.4 (m, 15H, H _ar ).

¹³ C NMR (125 MHz, CDCl ₃ ):

63.5 (d, J _cp = 2.17 Hz, CH ₂ ); 76.3 (d, J _CF = 7.08 Hz, C ₄ ); 87.2 ((Ph) ₃ C-); 123.8 (d, J _CP = 6.56 Hz, C ₃ ); 127.3 (C _ar ); 128.0 (C _ar ); 128.5 (C _ar ); 143.1 (C _ar ); 148.7 (d, J _CF = 279 Hz, C ₂ ); 164.3 (d, J _CP = 32.2 Hz, C = 0)

¹⁸ F NMR (300 MHz, CDC1 ₃ ): -76.5

MS (EI): 374 (M +); 299; 243; 165; 105.

Example 3: Preparation of Fluoro-2-trityloxymethyl-4-dihydro-furanone- (2S, 4S) of formula (IV) in which R is triphenylmethyl and X is fluorine.

Hydrogenation of unsaturated fluorolactone.

Compound 0.25 g of compound (II) (0.66 mmol), 10 ml of ethyl acetate and a spatula point of Pd / C (10% t, Aldrich) are added to a 25 ml flask ). The medium is hydrogenated at room temperature, at atmospheric pressure for 18 hours. The medium is filtered on a bed of celite which is washed with ethyl acetate. The organic phase is concentrated in vacuo. A white solid is obtained. Yield: 98%

Melting point: 176-179 ° C (litt: 174-176 ° C)

[α] _D : +2.45 (c 1.02; CHCl ₃ )

^{X X} NMR. (500 MHz, CDCl ₃ ): δ 2.33 (m, 1H, H _4a ); 2.60 (m, 1H, H _4b ); 3.26 (dd, J = 5 and 10.7 Hz, 1H, H _{1 <a} ); 3.40 (ddd, J = 0.7; 3.6 and 10.7 Hz, 1H, H ^ _j ,); 4.49 (m, 1H, H _s ); 5.20 (dt, J = 8.9 and 51.3 Hz, 1H, H ₃ ); 7.2-7.5 (m, 15H, H _ar ).

¹³ C NMR (125 MHz, CDC1 ₃ ):

32.5 (d, J = 19.7 Hz, C ₄ ); 65.7 (CH ₂ 0); 76.7 (d, J _CF = 6.4 Hz, C ₅ ); 87.1 (d, J _CF = 193.3 Hz, C ₃ ); 88.4 ((Ph) ₃ - C-); 128.7 (C _ar ); 129.4 (C _ar ); 130.0 (C _ar ); 144.7 (C _ar ); 172.5 (d, J _CF = 21, l Hz, C = 0).

¹⁸ F NMR (300 MHz, CDCl ₃ ): -130.8

MS (EI): 376 (M +); 299; 243; 165; 105.

Claims

1) An optically active compound or not of formula (I):

In which :

R is chosen from a hydrogen atom, a C ₁ alkyl group. ₆ or an optionally substituted aryl group,

X represents a halogen such as a fluorine, bromine, chlorine or iodine atom,

2) A compound according to claim 1, characterized in that in formula (1) R is a triphenylmethyl, tert-butyl or benzyl group.

3) An optically active compound or not according to one of claims 1 or 2, characterized in that it corresponds to formula (II):

In which R and X have the same meaning as in formula (I).

4) An optically active compound or not according to one of claims 1 or 2, characterized in that it corresponds to formula (III):

In which R and X have the same meaning as in formula (I).

5) A process for preparing a compound of formula (III) as defined in claim 4 consisting of a reaction for removing sulfur oxide from the compound of formula (II) as defined in claim 2.

6) A process for the preparation of a compound of formula (III) according to claim 5, characterized in that the compound of formula (II) is prepared by a halogenation reaction in the presence of a metal hydride and then of a halogenating agent for a phenylsulfinyl lactone compound of formula (V):

In which R has the same meaning as in formula (I).

7) A process for preparing a compound of formula (III) according to claim 6, characterized in that the compound of formula (V) is prepared by an oxidation reaction of a 2-phenylthio-alkoxy compound (or hydroxy or aryloxy) methyl-4-furanone (4H) of formulas (VI):

In which R has the same meaning as in formula (I).

8) A process for the preparation of a compound of formula (III) according to claim 7, characterized in that the compound of formula (VI) is prepared by a condensation reaction of the compounds of formula (VII):

in which R has the same meaning as in formula (I), with phenylthioacetic acid followed by a cyclization reaction of the product obtained by heating a toluene solution of said product under reflux. 9) A process for the preparation of a halogeno-2-alkoxymethyl (or hydroxy or aryloxy) -4-furanone- (4H) compound, optically active or not, of formula (IV):

In which R and X have the same meaning as in formula (I), characterized in that a compound of formula (III) as defined in claim 3 is subjected to a hydrogenation reaction in the presence of palladium on carbon .

10) A process for the preparation of a halogeno-2-alkoxymethyl (or hydroxy or aryloxy) -4-furanone compound

(4H) of formula (IV) according to claim 9, characterized in that the compound of formula (III) is prepared according to any one of claims 5 to 8.