ES2379925B1 - PROCEDURE FOR THE SYNTHESIS OF LACTONES DERIVED FROM PROPIONIC P-HYDROXYPHYL ACID - Google Patents

Abstract

Procedure for the synthesis of lactones derived from p-hydroxyphenyl propionic acid, in the form of mixtures of cis / trans diasteroisomers of formula (I) or (Ia), # **** IMAGE-01 **** # where n can take values 1, 2 and 3; R may be H or CH {sub, 3} and R {sub, 1} may be H or CH {sub, 3}, comprising: #a) Oxidation of the compound of formula (IV) or the corresponding naphthyl series (IVa) in the presence of oxalyl chloride and dimethylsulfoxide in dichloromethane at -78 ° C (Swern oxidation) # **** IMAGE-02 **** # where n can take values 1, 2 and 3; R can be H or CH {sub, 3} #b) Treat the product derived from the previous step with the brominated derivative (II) in the presence of a metal and a solvent or solvent mixture # **** IMAGE-03 * *** # where R {sub, 1} can be H or CH {sub, 3}.

Description

Procedure for the synthesis of lactones derived from p-hydroxyphenyl propionic acid.

Technical sector of the invention

The present invention relates to an improved process for the preparation of lactones derived from p-hydroxyphenyl propionic acid, of formula (I) and (Ia)

where n can take values 1, 2 and 3; R can be H or CH3 and R1 can be H or CH3 and where the protons Ha and Hb can have a relative configuration cis (cis diasteroisomer) or trans (trans diasteroisomer).

Background of the invention

The compounds that have the formula (I) are substances capable of interfering with different mechanisms of transmission of the activation signals in immunocompetent cells thus blocking cell proliferation processes (EP1284263). This may allow the therapeutic use of these substances in the processes accompanied by an inadequate proliferation of the cells of the immune system. This involves the procedures of inflammatory infiltration of the tissue with lymphocyte proliferation such as so-called autoimmune diseases and inadequate responses to infectious agents with induction of tissue damage mediated by the immune system, evidently also including malignant and benign lymphoproliferative processes. Lymphocyte proliferation also participates pathogenically in different chronic diseases such as amyloidosis, Alzheimer's type dementia, arteriosclerosis, etc., which can benefit from the use of these agents.

EP2070533 discloses the use of these compounds in the treatment of skin conditions, especially in the treatment of psoriasis.

EP1284263 describes the preparation of this type of compounds through derivatives of p-hydroxyphenyl propionic acid. This patent describes intermediate stages of oxidation with pyridinium chlorochromate in dichloromethane, obtaining yields of an oxidized intermediate product of around 50%, which considerably reduces the overall yield in obtaining the final product, which is mostly obtained as a diastereomer cis. In order to have the final product with an acceptable yield and for the process to be efficient and economically viable it is necessary to find a procedure whose reaction stages have high yields.

The usefulness of these products and their proven therapeutic activity necessitates the development of a process that allows obtaining them in a simple, economically viable and high yield way.

Accordingly, the present invention has as its object the description of an improved process for the synthesis of the compounds of formula (I) or (Ia) which allows their obtaining with optimized yields. Likewise, the synthetic route proposed in the present invention allows to obtain the compounds of formula (I) or (Ia) with a relative con fi guration between the protons Ha and Hb cis (cis isomers) or trans (trans isomers) depending on the reagents and conditions used in the last synthetic stage.

Description of the invention

The process of the present invention is an improved, economically and commercially feasible method for preparing compounds of formula (I) or the corresponding naphthyl series (Ia).

where n can take values 1, 2 and 3; R can be H or CH3 and R1 can be H or CH3 and where protons Ha and Hb can have a relative cis or trans con fi guration.

The procedure includes:

a) Oxidation of the compound of formula (IV) or the corresponding naphthyl series (IVa) to give the corresponding aldehyde (III) or (IIIa) respectively under Swern oxidation conditions (Mancuso, AJ; Brownfain, DS; Swern, DJ Org. Chem. (1979), 44, 23, 4148-4150).

Where R can be HCH3.

b) Treat the aldehyde (III), or that corresponding to the naphthyl series (IIIa), with the brominated derivative (II) in the presence of a metal to give the compound of formula (I), or (Ia) if performed with the corresponding naphthyl series

where R1 can be HCH3.

The compounds of formula (I) or (Ia) are obtained as mixtures of cis diastereomers (protons Ha and Hb are in relative arrangement cis) and trans (protons Ha and Hb are in relative arrangement trans). However, depending on the metal used in the last reaction stage (step b)) it is possible to obtain very enriched mixtures in one or another diastereomer, with diasteromic ratios around 95: 5.

The metal used in step b) is selected from zinc in the oxidation state (0) (Zn0) and tin in the oxidation state (0) (Sn0).

The possibility of obtaining the majority of lactones (I) or (Ia) with cis or trans relative stereochemistry depending on the metal used as promoter of the reaction is of great interest from the synthetic point of view.

Description of the drawings

To complete the description that is being made, a set of drawings is attached, where the following has been shown as an illustration:

Figure 1: 1H-NMR spectrum of the trans isomer of formula (I) with R = R1 = CH3 and n = 1.

Figure 2: 1H-NMR spectrum of the cis isomer of formula (I) with R = R1 = CH3 and n = 1.

Detailed description of the invention

The process of the present invention is a new, economically and commercially feasible improved method for preparing compounds of formula (I) or (Ia) indicated above.

The process of the present invention is summarized in the following scheme:

Where n can take values 1,2y3, and where R can be HCH3 and R1 can be H or CH3. "M" represents a metallic element, since the reaction between the aldehyde of formula (III) and the brominated derivative of formula (II) takes place in the presence of a metal.

In the same way the lactones (Ia) of the naphthyl series can be obtained.

First, the synthesis of aldehyde (III) from the corresponding alcohol (IV) is carried out through a Swern oxidation process, that is, in the presence of activated DMSO, low temperature oxalyl chloride (-78 ° C ) and subsequent addition of triethylamine.

The brominated derivative (II) can be easily obtained by treating the alcohol (V) with lithium bromide in the presence of a cation exchange resin.

The alcohol (V) is well known or can be prepared by methods well known in the state of the art.

Subsequently, the aldehyde (III) is reacted with the brominated derivative (II) to give the corresponding lactone of formula (I). The reaction between the compounds (II) and (III) can be carried out in the presence of different metals to give rise to the lactones (I) in the form of a mixture of cis / trans isomers very enriched in one or another isomer depending on the conditions . Thus, when the reaction between (II) and (III) takes place in the presence of tin (Sn0) and acetic acid in water / ethyl ether (1: 1) at reflux, the cis isomer is obtained mostly, in a trans / cis 5:95, while when carried out in the presence of zinc (Zn0) in saturated ammonium chloride / THF at room temperature, the majority is trans, in a trans / cis ratio of 95: 5.

The process of the present invention for obtaining the compounds of formula (I) or (Ia) is a great improvement in terms of overall performance by using an oxidation reaction that results in synthetic intermediates with very high yields. In addition, it offers the possibility of obtaining lactones (I) or (Ia) mostly as cis or trans diasteroisomers depending on the metal used as a promoter of the last synthetic stage.

Below are some illustrative examples of the present invention for obtaining aldehyde (III), brominated derivative (II) and lactones (I).

Example 1

Preparation of 3- (4-methoxyphenyl) -propanal from 3- (4-methoxyphenyl) -propanol

In a two-mouth flask fitted with an addition funnel at compensated pressure, an oxalyl chloride solution (123.3 mmol, 10 ml) in dichloromethane (120 ml) cooled to -78 ° C under an inert atmosphere is placed. On top of this solution, another dimethylsulfoxide (DMSO) (240.8 mmol, 17.2 ml) in dichloromethane (60 ml) is added dropwise, once the addition is finished, the resulting solution is stirred at -78 ° C for 5 min. The 3- (4-methoxyphenyl) -propanol (60.2 mmol, 10 g) dissolved in dichloromethane (120 ml) is added dropwise. The resulting solution is stirred at -78 ° C for 45 min., After which triethylamine (360 mmol, 50 ml) is added dropwise and allowing the resulting suspension to reach room temperature. Stirring is then maintained at that temperature until the starting product cannot be detected by HPLC-MS.

Once the starting product is consumed, the solution is added on saturated sodium bicarbonate and the aqueous phase is extracted with dichloromethane (3 x 100 ml), the organic extracts are dried over magnesium sulfate (MgSO4) and once filtered it is removed under pressure reduced The reaction crude is purified by column chromatography on silica gel using a 10: 1 hexane / ethyl acetate mixture as eluent, yielding 9.20 g (93%) of 3- (4-methoxyphenyl) -propanal with 96 % purity checked by HPLC-MS.

Spectroscopic data:

IR νm´ax (CHCl3) cm − 1: 2840, 2730, 1716, 1600, 1580, 1511, 1440, 1175, 1109, 1076, 814.

MS m / z (int. Rel.): 164 [M +] (23), 121 (100), 108 (30), 91 (25), 78 (20), 77 (16).

1HRMN (δ, CDCl3): 2.70 (t, J = 7.5 Hz, 2H, -CH2-), 2.91 (t, J = 7.3 Hz, 2H, phenyl-CH2-), 3.79 (s, 3H, phenyl-OCH3) , 6.84 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 9.60 (s, 1H, CHO).

13C NMR (δ, CDCl3): 27.11 (t), 45.38 (t), 55.09 (q), 113.75 (d), 113.84 (d), 129.10 (d), 129.15 (d), 132.21 (s),

157.94 (s), 201.72 (s).

Example 2

Preparation of methyl 2-bromomethyl-2-butanoate (II, with R1 = CH3)

On a solution of methyl 3-hydroxy-2-methylenenebutanoate alcohol (V, with R1 = CH3) (154 mmol, 20 g) in acetonitrile (0.5 M), lithium bromide (308 mmol, 26.7 g) are successively added and Amberlyst® 15 (1 g / mmol of alcohol (V)) at room temperature, the resulting suspension is vigorously stirred at room temperature for 6 h. Once the reaction is finished, it is filtered in vacuo to remove the acidic resin, washed with ethyl acetate (200 ml). The organic phase is washed successively with a saturated solution of sodium bicarbonate (100 ml) and water (100 ml). It is dried over MgSO4 and the solvent is removed under reduced pressure, obtaining 26 g (91%) of the methyl 2-bromomethyl-2-butanoate compound with 96% HPLC purity.

Example 3

Preparation of compound 5- (4- (methoxyphenylethyl) -4-methyl-3-methylene-dihydrofuran-2 (3H) -one as mixtures of cis / trans diasteroisomers in 95: 5 ratio

A suspension containing 3- (4-methoxyphenyl) -propanal (700 mg, 4.26 mmol), alkyl bromide (II, with R1 = CH3) (1.16 g, 6.0 mmol), tin (Sn0) (708 mg, 6.0 mmol) and acetic acid (25 μl, 10% mol in water / ethyl ether (1: 1 4 ml) is heated at reflux for 96 h, then filtered through celite and washed said celite with ethyl acetate.The organic phase is washed with a saturated solution of sodium chloride, dried over MgSO4, filtered and the solvent is removed under reduced pressure.The residue obtained is purified by silica gel column chromatography using a 10: 1 dichloromethane / hexane mixture, to obtain 5- (4- (methoxyphenylethyl) -4-methyl-3-methylene-dihydrofuran-2 (3H) -one as a mixture of cis / trans diastereomers in relative ratio 95: 5 with 55% yield

Spectroscopic data of cis diasteromer:

IR νm´ax (CHCl3) cm − 1: 2954, 2836, 1759, 1663, 1611, 1583, 1510, 1455, 1324, 1300, 1244, 1178, 1150, 1123, 1098, 1034, 945, 830, 815.

1H NMR (δ CDCl3 500 MHz): 1.13 (d, 3H, J = 7.02 Hz), 1.74-1.77 (m, 2H), 2.62-2.66 (m, 1H), 2.78-2.84 (m, 1H), 3.08- 3.12 (m, 1H), 3.77 (s, 3H), 4.47-4.48 (m, 1H), 5.51 (d, 1H, J = 2.6 Hz), 6.20 (d, 1H, J = 2.8 Hz), 6.82 (d , 2H, J = 6.56 Hz), 7.10 (2H, 2H, J = 6.56 Hz).

13C NMR (δ, CDCl3, 125 MHz): 13.84, 30.8, 32.9, 37.39, 55.3, 79.98, 113.9 (2C), 120.8, 129.5 (2C), 132.9, 140.76, 158.02, 170.35 ppm.

Example 4

Preparation of compound 5- (4- (methoxyphenylethyl) -4-methyl-3-methylene-dihydrofuran-2 (3H) -one as mixtures of cis / trans diastereomers in proportion 5:95

On a suspension of zinc (Zn0) (1.05 g, 16 mmol) and 3- (4-methoxyphenyl) -propanal (1.33 g, 8 mmol) in saturated aqueous ammonium chloride (8 ml), strongly stirred, add the brominated compound (II, with R = CH3) (3.1 g, 16 mmol) dissolved in tetrahydrofuran (THF) (16 mmol) at room temperature, dropwise. The resulting solution is stirred at room temperature for 21 h. It is then filtered through celite, then washed with ethyl acetate. The aqueous phase is extracted with ethyl acetate (3x10 ml), dried over MgSO4 and the solvent is removed under reduced pressure.

The product was purified by silica gel column chromatography to obtain 5- (4- (methoxyphenylethyl) -4-methyl3-methylene-dihydrofuran-2 (3H) -one as a mixture of cis / trans diastereomers in relative proportion 5: 95 with a 60% yield.

Spectroscopic data of the trans diasteromer:

IR νm´ (CHCl3) cm − 1: 2934, 1764, 1662, 1611, 1583, 1512, 1461, 1317, 1301, 1247, 1178, 1143, 1123, 1098,

ax

1034, 948, 830, 814.

1H NMR (δ CDCl3 500 MHz): 1.19 (d, 3H, J = 6.86 Hz), 1.89-1.96 (m, 2H), 2.66-2.68 (m, 2H), 2.78-2.83 (m, 1H), 3.76 ( s, 3H), 3.94-3.95 (m, 1H), 5.51 (d, 1H, J = 2.7 Hz), 6.21 (d, 1H, J = 2.5 Hz), 6.82 (d, 2H, J = 6.71 Hz), 7.10 (2H, 2H, J = 6.71 Hz).

13C NMR (δ, CDCl3, 125 MHz): 16.86, 30.67, 36.87, 39.99, 55.19, 83.94, 113.88 (2C), 120.90, 129.28 (2C), 132.74, 140.77, 157.94, 170.20 ppm.

Claims (10)

1. Procedure for obtaining mixtures of cis / trans diastereomers of formula (I) or mixtures of cis / trans diastereomers of formula (Ia), with the cis diastereomer having the protons Ha and Hb in relative configuration cis and the trans diastereomer which has protons Ha and Hb in relative trans con fi guration where n can take values 1,2y3; R can be HCH3 and R1 can be HCH3. It comprises: a) Oxidation of the compound of formula (IV), or the corresponding naphthyl series (IVa), in the presence of oxalyl chloride and dimethylsulfoxide in dichloromethane at -78 ° C (Swern oxidation) where n can take values 1,2y3yR can be HCH3. b) Treat the product derived from the previous step with the brominated derivative (II) in the presence of a metal and a solvent or solvent mixture where R1 can be HCH3. 2. Method for obtaining mixtures of cis / trans diastereomers according to claim 1, characterized in that the brominated derivative (II) is obtained by reaction of the alcohol (V) of the formula: with lithium bromide in the presence of Amberlyst® 15 and acetonitrile as solvent.

3.

Process for obtaining mixtures of cis / trans diastereomers according to claim 1, wherein the metal used in step b) is selected from zinc in the oxidation state (0) (Zn0) and tin in the oxidation state (0) (Sn0) .

Four.

Process for obtaining mixtures of cis / trans diastereomers according to claim 3 wherein the metal used in step b) is Zn0 in a solvent mixture consisting of saturated aqueous ammonium chloride and tetrahydrofuran.

5.

Process for obtaining mixtures of cis / trans diasteroisomers according to claim 4 wherein the molar ratio between Zn0 and brominated derivative (II) is 1: 1.

6.

Process for obtaining mixtures of cis / trans diastereomers according to claim 3 wherein the metal used in step b) is Sn0 in a solvent mixture consisting of water and ethyl ether and in the presence of acetic acid.

7.

Process for obtaining mixtures of cis / trans diasteroisomers according to claim 6 wherein the molar ratio between Sn0 and brominated derivative (II) is 1: 1.

8.

Process for obtaining mixtures of cis / trans diasteroisomers according to claim 1, wherein R1 represents a methyl group and R represents another methyl group.

9.

Process for obtaining mixtures of cis / trans diastereomers according to claim 1 wherein the mixture of diastereomers of formula (I) or (Ia) obtained in step b) is purified by column chromatography.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201001288 SPAIN Date of submission of the application: 06.10.2010 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: C07D307 / 58 (2006.01) RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

TO

EP 1284263 A1 (SUPERIOR SCIENTIFIC RESEARCH COUNCIL), claims, diagrams 1 and 2, page 16 1-9

TO

Journal Medicinal Chemistry 2002, volume 45, pp 2358-2361. "Synthesis and antiproliferative activity of a new compound containing an alpha-methylene-gamma-lactone group", scheme 1, page 2359 left column 1-9

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 06.30.2011

Examiner M. Fernández Fernández Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201001288 Minimum documentation sought (classification system followed by classification symbols) C07D Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENTIONS, EPODOC, WPI, CAS, REGISTRY State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201001288 Date of Completion of Written Opinion: 05.31.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-9 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-9 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201001288 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

EP 1284263 A1 (HIGHER SCIENTIFIC RESEARCH COUNCIL) FROM 02/19/2003

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The application refers to a method of synthesis of lactones derived from p-hydroxyphenyl propionic acid, with a majority of cis / trans diastereoisomers, of formulas (I) or (Ia) (claim 1) comprising the following two steps : -oxidation of the alcohols of formulas (IV) or (IVa) to the corresponding aldehydes using Swern oxidation -reaction of the product obtained with the brominated derivative of formula (II), in the presence of a metal (Zn or Sn). Document D1 discloses a process for obtaining the compounds of formula (I) of the application (see formula (I) of claim 1 of D1) according to diagrams 1 and 2 (see pages 7 and 8 of D1), which consists of the reaction of 3- (4-methoxyphenyl) propanal with methyl 2-bromomethyl-2-propenoate (see page 16 of D1); the procedure described in the application differs from that disclosed in D1 in obtaining the aldehyde from the corresponding alcohol, in D1 it is used as an oxidant pyridinium chlorochromate (page 12 of D1 paragraph 0045), in the procedure described in the application it is used the oxidation of Swern (oxalyl chloride and dimethylsulfoxide in dichloromethane), this being preferable in terms of performance and industrial application. In addition, this procedure has the advantage of being able to obtain mostly the cis or trans diastereoisomer according to whether the reaction is carried out in the presence of zinc or tin. Consequently it follows that the procedure of the application presents novelties not foreseen in the state of the art, so that claims 1-9 of the application are considered to have novelty and inventive activity, as established in Art. 6.1 and 8.1 of Patent Law 11/1986. State of the Art Report Page 4/4