FI64136C - PROCEDURE FOR FRAMSTATION OF AV D-2- (6-METHOXY-2-NAPHTHYL) -PROPIONSYRA - Google Patents

Description

I55F1 [B] (11) ANNOUNCEMENT 64176

JgfiSjft lJ '' UTLÄGGNINGSSKRIFT ° ^ ° C 05) -; 3 '^ ^ (51) Kv.ik.W.ci) C 07 C 59/64, 0 07 B 19/00 FINLAND — FINLAND (11) p * tenuih * k * mu * —p «« * t * n * ökninj ($ (22) Hakcmlipiivi - AraAknlngwiaf 22.0 (. 77 (FI) (13) Alkupttvft — Glltlghutsdag 22.07 * 77 (41) Has become public - BlivK offuntil * 29 · 01.73

Patent and registration authorities NihtiviUpron j. when «L | ultaUun pvm. - _. _

Patent- OCh regitterstyrelsen AntBkan utlagd och utl.skrtfnn publkerid 30.Ob.ö3 (32) (33) (31) Pyrd «« y «uoikeui — Bejird prtoritet 28.07.76

Italy-Italy (IT) 25778 A / 76 (71) (72) Raffaele Pessina, Viale Regina Giovanna 2k> Milan, Italy-Italy (lT) (7 * 0 Leitzinger Oy (5U) Method d-2- (6-methoxy The present invention relates to a new process for the preparation of d-2- (6-methoxy-2-naphthyl) propionic acid, for the preparation of d-2- (6-methoxy-2-naphthyl) propionic acid. with the following structural formula:

- CH-COOH

"3

The patent literature (e.g., U.S. Patent 3,694,476, issued September 26, 1972, English Patent 1,301,439 and French Patent 2,195,438, issued March 8, 1974) discloses various methods for preparing and dissolving 2- (6-methoxy-2-naphthyl) propionic acid as an optical. The levorotatory isomer of this compound has recently been found to play a significant role in therapy.

2 64136 These methods start from raw materials which are expensive and difficult to obtain so pure that the synthesis proceeds favorably.

It has now surprisingly been found, which is the subject of the present invention, a new synthetic method which can be used on an industrial scale. The process starts from 6-alkoxy-2-propionaphthone, which is readily available in very pure form and in very good yields.

In the separation of optical antipodes, the present invention uses an optically active base, more specifically a D (-) o (-phenylglycine ethyl ester base) which is inexpensively available from industrial manufacture.

The method according to the present invention can be represented schematically as follows: co-ch2-ch3 co-ch-ch 3

R0 RO CHO

(I) (II) ^^ n ^ sS — co-c-ch ^ r ^ V ^^ r-co-cox _) I li J _ \ I | _v N2 CH3 (III) (IV)

_ —CH-COOH ^ COOH

(V) (VI) 641 36 3 wherein: R is a "lower alkyl" group? the term covers straight-chain or branched primary, secondary and tertiary alkyl groups having up to 6 carbon atoms in configuration, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n -hexyl and the like? X is -NHCgHg, -NHCgH ^ CH8 (° "m_» P "isomers), -NHCgH ^ Y (where Y is halogen, in the o-, m-, p-position), -NHCgH4NO2 (o-, m-, p-isomers), NHCl 3 gHy, and the like.

In the present reaction, in a first step, 6-alkoxy-2-propionaphthone (I) is reacted with an alkyl formate (such as methyl, ethyl, propyl formate) in an anhydrous organic solvent in the presence of a strong base to give α-foryl ketone (II). Any conventional organic solvent inert to the reaction components can be used in this reaction.

A suitable solvent is acetonitrile but other anhydrous organic solvents may also be used.

Suitable bases include sodium methylate, sodium ethylate and / or, in the case of an aprotic solvent, sodium, sodium amide and sodium hydride. The reaction is carried out at a temperature in the range of 0 to 70 ° C, preferably 20 to 40 ° C.

Reaction time depends on temperature: Reaction times are usually 1-14 hours? the best yields are obtained with reaction times of 10 to 12 hours when the reaction is carried out at a temperature of 25 to 30 ° C.

The ratio of reactants can vary within wide limits:

The best yields are obtained when the ratio of 6-alkoxy-2-propionaphthoate: alkyl formate: base is 1: 1.3 s 1.5 stoichiometric.

The compounds of formula (II) are separated from the reaction mixture by conventional techniques. For example, the reaction mixture can be evaporated to dryness in vacuo, the residue can be re-treated with water and the non-hydrolysed impurities can be removed with ethyl ether. The aqueous phase, cooled with water and ice, is acidified with dilute acid. Both organic and inorganic acids such as acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid can be used for this purpose. Hydrochloric acid and sulfuric acid are best used. The precipitate formed during acidification is filtered on a Biichner funnel, washed with water and crystallized from a suitable solvent.

Alternatively, compounds of formula (II) may be isolated by adding an inert solvent to the reaction mixture to precipitate the sodium salt of the α-methyl ketone formed during the reaction, the solid separated by filtration on a Biichner funnel and then dissolved in water: The desired product is acidified as described above.

In the second step of the present invention, d-formyl ketones (II) are reacted with sulfanilazide in an organic solvent in the presence of a tertiary amine base to give <x-diazoketones (III).

Said sulphanilazide may be an aliphatic sulphanilazide such as methanesulphanilazide or an aromatic sulphanilazide such as benzenesulphanilazide or tosyl azide.

The best results are obtained in the reaction when said sulfanil azide is prepared extempore in the same reaction solvent and used immediately in the reaction, thereby avoiding even partial decomposition of the sulfanil azide. Any solvent that is inert to the reaction components can be used in the reaction. Suitable solvents at this stage include aromatic hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like.

Tertiary organic bases may be aliphatic bases, such as triethylamine, or heterocyclic bases, such as pyridine.

The reaction can be carried out at a temperature in the range of -5 to + 50 ° C. Optimum temperatures are in the range of 0 to 20 ° C. The reaction time, which depends on the selected temperature, is between 0.5 and 2 hours.

The molar ratio of reaction components may vary. The best results are obtained when the molar ratio of crt-formyl ketone: sulfanilazide: base is 1: 1 s 2.

The use of an additional base is crucial because, in addition to having a positive effect on the progress of the reaction, it also aids in the subsequent removal of the N-formylsulfanamide formed as a by-product.

The compounds of formula (III) are separated from the reaction mixture using conventional methods.

For example, the mixture may be washed first with water and / or an aqueous alkaline solution and then with water until neutral. The separated organic phase can be evaporated to dryness under reduced pressure and low temperature to prevent possible decomposition of the diazo derivative.

Alternatively, the reaction mixture neutralized as described above can be used directly, without isolating diazoketone, in the third step of the process of the present invention, as described below.

In the third step, o (-diazoketones (III) are reacted with a primary aromatic amine in the presence or absence of an inert organic solvent to give arylamides of 2- (6-alkoxy-2-naphthyl) -propionic acids (IV).

Alternatively, the reaction can be carried out by adding the diazoketone solution obtained above dropwise directly to the aromatic amine heated to a suitable temperature and continuously distilling off the solvent. The reaction can be carried out at temperatures between 6 6 41 36 100 and 180 ° C but most preferably between 130 and 150 ° C.

Any aromatic amine can be used in the reaction: However, aniline, toluidines and naphthylamines are economically preferred.

The molar ratios of the reaction components can be varied within wide limits: The best results are obtained when the ratio of λ-diazoketone to aromatic amine, calculated in moles, is 1: 4.

To separate the compounds of formula (IV), the reaction mixture is poured into dilute acids and the precipitate is filtered through a Buchner funnel, washed with water until neutral and then with a small amount of lower aliphatic alcohol and finally crystallized from a suitable solvent.

Alternatively, when the reaction is carried out in an organic solvent, it is convenient to distill off the solvent under reduced pressure before the acid treatment. Both organic acids such as acetic acid, p-toluenesulfonic acid and inorganic acids such as hydrochloric acid, sulfuric acid can be used.

The compounds of formula (IV) are then hydrolysed to the compound of formula (V) which is directly alkylated to 2- (6-methoxy-2-naphthyl) -propionic acid (VI).

The hydrolysis can be performed using a solution of a strong organic or inorganic acid. Examples of acids include trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid.

The hydrolysis can be carried out at temperatures of at least 35 ° C, preferably 60 ° C - the reflux temperature of the mixture.

The time required for the hydrolysis depends on the nature of the radicals R and X and the reaction temperature: 2-7 hours is usually sufficient.

The compound of formula (V) is isolated from the reaction mixture by conventional means. 641 36 7 Sat with technology. For example, the mixture can be concentrated in vacuo to a small volume, poured into water and the precipitated precipitate is separated on a Blichner funnel and washed with water until neutral.

The crude 2- (6-hydroxy-2-naphthyl) -propionic acid (V) thus obtained can be alkylated by treatment with an alkylating agent in an alkaline medium.

Alkylating agents useful in this reaction include, for example, dimethyl sulfate, dimethyl carbonate, methyl bromide, and the like. Water and / or lower aliphatic alcohols are suitable solvents. Sodium trihydrate, potassium hydrate, sodium carbonate and potassium carbonate are useful in forming the alkaline environment. The reaction can be carried out at a temperature of 40 ° C to the reflux temperature of the mixture. Optimum temperatures range from 55 to 70 ° C. The time required depends on the reaction temperature: The reaction is usually completed within 1.5 to 3 hours.

To separate the compound of formula (VI), the reaction mixture is acidified with a solution of a strong organic or inorganic acid and the separated product is filtered through a BUchner funnel. After washing to neutral with water, 2- (6-methoxy-2-naphthyl) -propionic acid (VI) is dried in vacuo at 50 ° C in a state sufficiently pure for the next reaction.

Separation of 2- (6-methoxy-2-naphthyl) propionic acid into its optical antipodes can be accomplished with a variety of optically active bases, many of which are included in the aforementioned patent literature.

It has now been found that D (-) - of-phenylglycine amino acid ethyl ester prepared on an industrial scale is particularly suitable for this purpose, with the additional advantage of a low cost. The separation is conveniently carried out with a molar ratio of acid (VI) to optically active base of 2: 1, in a solvent which is able to dissolve the reactants completely and at the same time poorly dissolves the salt formed. A suitable solvent is water-saturated ethyl acetate. D-2- (6-methoxy-2-naphthyl) propionate of D (-) - phenylglycinate ethyl is isolated from the reaction mixture by slowly stirring 8,641,36 solutions cooled to 10 ° C. The crude product obtained has an optical purity of about 80 S and can be improved by washing with wet ethyl acetate. Separation of D-2- (6-methoxy-2-naphthyl) propionic acid can be accomplished by treating the optically active salt with mineral acids. It has a melting point of 154-156 ° C after crystallization from ethyl acetate and I + JD + 66 ° (C »1%, in chloroform).

The following example illustrates the method of the present invention.

Example 6-Methoxy-2- (α-formylpropionyl) -naphthylene (II)

Solution containing 6-methoxy-2-propionaphthone (I) prepared by the method of Haworth and Scheldrick - J. Chem. Soc. 1934, 864J (32.1 g, 0.15 mol) and ethyl formate (14.8 g, 0.20 mol) in 450 mL of anhydrous acetonitrile were added dropwise to a stirred suspension of sodium hydride (75% to 7.2 g, 0.225 mol). ) at a temperature of 23 to 25 ° C. The addition was completed in two hours and then the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, the residue was taken up in about 300 ml of water and the insolubles were extracted with ether. The aqueous solution cooled in a water / ice bath was acidified with 1: 3 hydrochloric acid. The solid formed was collected on a Buchner funnel, washed neutral with water and crystallized from ethanol. 22.5 g of 6-methoxy-2- (ε-formylpropionyl) -naphthalene (II) were obtained.

Yield: 63%, m.p. 151oCe

Analysis: C15H1403 Result: C »74.18% H = 5.79%

Calcd: C * 74.36% H = 5.82% IR (nujoi) ν max - 1640 cm -1 NMR (acetone - d 6) δ 1.89 (3H, s, CH 3), 3.95 (3H, s, OCH 3), 7.2-8.2 (7 H, m, aromatic and CHO)

II

641 36 9 6-Methoxy-2- (ol-diazapropionyl) -naphthalene)

Solution containing 4 g (0.02 moles) of p-toluenesulfanilazide CPrepared by the method of M. Regitz, J. Hocker and A. Liedhegener - Org. Synt. Coll., Vol. 5, page 179J in 15 ml of methylene chloride, was added dropwise with stirring and cooling in a water / ice bath over 30 minutes to a solution containing 4.84 g (0.02 mol) of <* - formyl ketone (II) and 4 g (0.04 mol) of triethylamine in 60 ml of methylene chloride. The mixture was stirred at room temperature for one hour. The mixture was then diluted with 150 mL of methylene chloride, washed first with 0.25 N potassium hydrate and then with water until neutral. The product was dried, the solvent was evaporated under reduced pressure and the residue was treated with isopropyl ether. Diazaketone (III) was obtained by filtration on a Biichner funnel as a yellow solid - m.p. 109-111 ° C (decomposes). The yield was 3.6 g or 74%. Acetonistda recrystallized sample m.p. was 114-115 ° C (decomposes).

Analysis: C 14 H 12 N 2 O 2 Result: C »70.21% H = 5.11% N = 11.49%

Calc .: C * 69.98% H = 5.04% N = 11.66% IR (nujol) VN 2 * 2090 cm -1 NMR (acetone-d 6) β 2.17 (3H, s, CH 3) 3, 94 (3H, s, OCH 3) 7.1-8.2 (6H, m, aromatic).

2- (6-Methoxy-2-naphthyl) -propionic acid anilide (IV) 1 g of Λ-diazacetone (III) was added in small amounts while stirring to 10 ml of aniline heated to 150 ° C. The addition was completed in 15 minutes. The mixture was allowed to stand for a further 30 minutes at 150 ° C, then allowed to cool and poured into 120 ml of cold, about 1N hydrochloric acid. The solid formed was collected on a Biichner funnel and cooled with a small amount of ethanol. There was thus obtained 0.51 g of anilide (IV),

Sp. 133-135 ° C. After crystallization from chloroform, the product Sp. was 138 ° C.

641 36 ίο

Analysis: C20H19NO2 Result: C * 78.90% H = 6.33% N = 4.42%

Calc .: C = 78.66% H = 6.27% N - 4.59% IR (nujol) Vjjj = 3300 λmax = 1660 cm -1 NMR (CDCl 3) δ 1.64 (34, d, J = 7 Hz, CH 3) 3.6-4.1 (4H, complex signal, OCH 3 and CH), 7.0-7.9 (11H, m, aromatic).

2- (6-Methoxy-2-naphthyl) -propionic acid (VI)

A solution of 3 g of anilide (IV) in 30 ml of concentrated hydrochloric acid, 10 ml of water and 40 ml of acetic acid was refluxed for four hours with stirring. Thereafter, most of the solvent was evaporated off under reduced pressure, and the residue was poured into water. The solid formed was collected on a Buchner funnel and washed with water until neutral. The product was almost pure 2- (6-hydroxy-2-naphthyl) -propionic acid (V) dissolved directly in 30 ml of 1N sodium hydrate. To this was added 3.8 g of dimethyl sulfate. The solution was heated at 60 ° C for two hours, allowed to cool to room temperature and acidified with dilute hydrochloric acid. The solid was collected on a Buchner funnel and washed with water until neutral. 1.75 g of 2- (6-methoxy-2-naphthyl) -propionic acid (VI) were obtained, yield 74%.

d-2- (6-methoxy-2-naphthyl) propionic acid 23 g (0.1 mol) of dl-2- (6-methoxy-2-naphthyl) propionic acid (VI) were dissolved in 150 ml of ethyl acetate saturated with water. At a temperature of 10θς. 9 g (0.05 mol) of D (-) - O'-phenylglycine ethyl ester dissolved in ethyl acetate were added. The reaction was started with 50 mg of ethyl D (-) - <X-phenylglycinate d-2- (6-methoxy-2-naphthyl) propinate. Crystallization was allowed to proceed for six hours. The product was filtered at 10 ° C, washed with 15 ml of ethyl acetate to give 12 g of a salt with an optical purity of 80% and a m.p. 110 ° C. Treatment of the salt with ethyl acetate increased the optical purity to 90%.

641 36 11

The resulting salt was treated with a mixture of 100 ml of ethyl acetate, 100 ml of water and 10 ml of concentrated hydrochloric acid. The organic phase was separated, washed with water and evaporated to dryness under reduced pressure. Crystallization of the residue from ethyl acetate gave 5 g of d-2- (6-methoxy-2-naphthyl) -propionic acid, m.p. 154-156 ° C. [Α] D + + 66 ° (c = 1%, in CHCl 3).

Claims (2)

1. Menetelmä d-2- (6-methoxy-2-naphthylyl) -propionihapone valmistamiseksi, tunnettu siitä, one menetelmään kuuluu vaihet, joissa: (a) 6-methoxy-2-propionafonateinate acid reagoimane methylyl, ethylylatin , only mukana mahdollisesti on vedetöntä organaanista liuotinta, cut acetonitrile, yes only mukana on ylimäärä vahvaa emästä, cut sodium metlaattia tai sodium ethyllaattia yes / tai, kun käytetään aproottista liuotinta, sodium hydride, sodium, sodium well up to 20 ° C and 25 ° C, 1 to 14 tunnels, parhaites 10 to 12 tunnels of aikana, jolloin such as 6-methoxy-2 - (<* - formyl-propionyl) -naphthaleneia, yoke erotetane reaction oxesta haihduttamalla liuotin kuiviin, jäänös käsitellään vedellä, pestään eetterillä, erotetaan faasit ja tehdään vesifaasi happameksi; (b) 6-methoxy-2- (o-formyl-propionyl) -naphthalene acetate reagoimaan alifaattisen tai aromaattisen sulfaniiliatsidin chance inertissä organaanisessa liuottimessa, only mukana on ylimäärä tertiäistä organaanista emästä, suitable - 20 ° C, 0.5-2 tonne aikana, jolloin such as 6-methoxy-2- (o-diatsopropionyl) naphthaleneia, joka voidaan erottaa reactioseoxesta pesemällä ensin vedellä tai vesipitoisella alkalilla ja sen jälkeen vedelläet able to neutralize kuiviin tyhjössä alhaisessa fitpötilassa tai vaihtoehtoisesti käyttämällä liuos suoraan seuraavassa vaiheessa liuotinta haihduttamatta; (c) 6-Methoxy-2 - (<* -diatsopropionyl) -naphthalene-acetate reagoimaan ylimäärän känna primärististä aromaattista amininia, only mukana mahdollisesti on inertti organinen liuotin, suitable mass 100-180 ° C, the type 130 - 150 ° C lakkaa, jolloin saadaan 2- (6-methoxy-2-naphthylyl) -propionihapone aryylamidia, joka erotetaan reactionoxesta tekemällä happameksi ja suodattamalla tai, only käytetään inerttiä organistaista liuotinta, poistamalla liuotin (d) hydrolysoidane 2- (6-methoxy-2-naphthylyl) -propionihapone aryylamide amide couumentamalla sitä yhdessä vahvan organaanis tai epäorgaani II 13 64136 sen yes, parhaiten 60 ° C - refluxine inhalation, can be hydrolysed on tapahtunut loppuun, jolloin such 2- (6-oxy-2-naphthylyl) -propionihappoa, joka erotetaan tislaamalla liuotin osittain pois tyhjössä, laimentamalla (e) touching 2- (6-oxy-2-naphthylyl) -propionihappoate acetate reagoimane alkylointleneen, cut dimethylylsulfaatin chance alkalisse germic acid impermissassis suitable for 40 ° C - seoxen refluxointilampötila, para70 , jolloin such as 2- (6-methoxy-2-naphthylyl) -propionihappoa, joka erotetaan tekemällä reactioseos happameksi, suodattamalla ja kiteyttämällä acetone-hexaanista; yes (f) dl-2- (6-methoxy-2-naphthylyl) -propionihappo erotetaan optisiksi antipodeikseen, valmistetaan diastereoisomeriset suolat optisesti activiivisen emäksen kanssa ja erityisesti D (-) - et ethyl acetate, erotetane diastereomerite suolate tai isomerite fractiokiteyttämällä, jolloin mineralihapolla suoritetun jakamisen jälkeen saadaan d-2- (6-methoxy-2-naphthylyl) propionic acid. 14 641 36 Process for the preparation of d-2- (6-methoxy-2-naphthyl) -propionic acid, characterized in that the process consists of steps in which (a) 6-methoxy-2-propionaphtonate is reacted with methyl, ethyl - or propyl formate, optionally in the presence of anhydrous organic solvent, such as acetone nitrile, and in the presence of an excess of a base such as sodium methylate or sodium ethylate and / or use of an aprotic solvent, sodium, sodium amide and sodium hydride, at a temperature of 0 - 70 ° C, preferably 20 - 25 ° C, for 1-14 hours, preferably for 10-12 hours, to obtain 6-methoxy-2- (*-formylpropionyl) naphthalene, which is separated from the reaction mixture by evaporate the solution, the residue is treated with water, washed with ether, the phases are separated and the aqueous phase is made sury (b) 6-methoxy-2 - (< an excess of a tertiary organic base, within the temperature range -5 - + 50 ° C, preferably 0-20 ° C, for 0.5 - 2 hours to obtain 6-methoxy-2- (oi-diazopropionyl) naphthalene, which can be separated from the reaction mixture by first washing with water or with aqueous alkali and then with water until a neutral state is achieved, by evaporating in vacuo at low temperature or alternatively by directly using the mixture in the following step without evaporating the solvent (c) 6-methoxy-2- («- diazopropionyl) - the naphthalene is reacted with an excess of a primary aromatic amine optionally in the presence of an inert organic solvent, at a temperature of 100 - 180 ° C, preferably 130 - 150 ° C, until the evolution of nitrogen stops, leaving an arylamide of 2- (6). (methoxy-2-naphthyl) -propionic acid is obtained, which is separated from the reaction mixture by acidifying it and filtering or, when an inert organic solvent is used, by removing the solvent in vacuo, acidifying the acid and filtration (d) 2- (6). (methoxy-2-naphthyl) propionic acid ylamide is hydrolyzed by heating it together with a strong organic or inorganic acid solution in a water-miscible solvent, such as acetic acid or li