CZ2012768A3 - Process for preparing 5-halosubstituted 6-methyl-{beta}-tetralones - Google Patents

Abstract

A process for the preparation of 5-halo-substituted 6-methyl-beta-tetralones of formula (I), which proceeds in 6 steps, the step of Friedel and Craft cyclization of acid chlorides of general formula (IV) being an important step. The cyclization is carried out using Lewis acids and in the presence of inert organic solvents. Another essential step is the isomerization of the epoxides of formula VII.

Description

The present invention relates to a process for the preparation of 5-halo-substituted 6-methyl-β-tetralones of general formula (I).

The compounds of formula I are novel and are important intermediates in the synthesis of terutroban.

BACKGROUND OF THE INVENTION

For the preparation of β-tetralones, there are many procedures in the literature, for example cyclization of diazoketones under catalysis with Rh (II) salts, thus producing a tetralone lacking a methyl group (Chandra et al Org Lett 2007, 9, 5027-5029).

Using the method, the title tetralone was prepared from 3- (2-bromo-3-methylphenyl) propanoyl chloride, which by reaction with diazomethane afforded the corresponding diazoketone, which was converted to the desired tetralone in good yield after acid catalysis with Rh (II). Unfortunately, in view of the safety of working with diazomethane on large scales, this short synthesis for industrial use is very problematic.

Another variant for the preparation of key β-tetralone was based on various intermediates for the preparation of 1-bromo or 1-chloro-4- (2-bromo-3-methylphenyl) butan-2-one and assuming cyclization to the desired intermediate. Although similar reactions have been described (eg, Synthetic Communications, 24 (18), 2557-2562 (1992); J. Med. Chem., 1991, 34 (3) 1164-1176; J. Org. Chem, 69 (5)). 2004 1629-1633) and utilized, the influence of substituents at given positions does not allow this cyclization reaction. Another approach reported in the literature for the preparation of tetralones utilized the reaction of 5- (2-bromo-3-methylphenyl) -3-oxopentanoic acid methyl ester with iodobenzene diacetate and CuCl cyclization (Tetrahedron Letters, 38 (25) 4333-4336, 1997; Org Chem 74 (1) 470-473, 2009); neither can the desired substituted tetralones be prepared by this method.

Tetralones can also be prepared by progressive construction (J. Org. Chem., 49 (22), 4226-4237) - Scheme 1 starting from 2-bromo-1-methylbenzene (1), which is brominated to benzyl bromide 2, converted to nitrile 3 from which acid 4 is prepared. Reduction gives alcohol 5, which is converted to bromide 6, and reacted with diethyl malonate to prepare diethyl ester 7, which after saponification affords dicarboxy acid 8 and decarboxylation affords 4- (2- bromo (phenyl) butanoic acid (9). Cyclization afforded α-tetralone 10 (5-bromo-3,4-dihydronaphthalen-1 (2H) -one).

Similarly, we prepared from 2-bromo-1,3-dimethylbenzene by the above procedure

5-bromo (-6-methyl-3,4-dihydronaphthalen-1 (2H) -one)

Scheme 1

However, this is a multi-step synthesis and the resulting yield of nine reactions to α-tetralone is about 20 (%. Our procedure described below has a significantly smaller number of reaction steps (3 isolated intermediates) and the resulting yield of α-tetralone reaction sequence is about 6 ^ O.

This α-tetralone is further reduced to alcohol and dehydrated to 8-bromo-7-methyl-1,2-dihydronaphthalene. After oxidation to the epoxide, the key β-tetralone is prepared.

The literature describes the reactions of α-tetralone 10 to β-tetralone 14 (Scheme 2) first by reduction to alcohol 11, then dehydration to dihydronaphthalene 12, followed by epoxidation of MCPBA (m-chloroperoxybenzoic acid) and opening of the epoxide under acid catalysis such as ZnB (J). Med Chem 1989, 32 (9), 2128-2134), BF 3 * Et 2 O, p-toluenesulfonic acid, Dowex resin (Synth. Commun. 1990, 20 (12), 1751-1756), aqueous HCl.

OH

We have advantageously used the crude alcohol after the reduction to dehydrate to dihydronaphthalene. Epoxidation was carried out with Oxone instead of traditional m-chloroperbenzoic acid (MCPBA) and after a rearrangement of the crude epoxy solution catalyzed by zeolite K-10 (instead of a strong mineral or Lewis acids used for similar transformations) gave the desired β-tetralone. This catalyst is readily removed after filtration by filtration.

SUMMARY OF THE INVENTION

The object of the invention is to produce 5-halo-substituted 6-methyl-β-tetralones of the general formula 1,

wherein X represents halogen, such as chlorine, bromine or iodine, of the key intermediates in terutroban synthesis, which is based on the synthesis of 5-halogen substituted 6-methyl-α-tetralones of the general formula Ιζ.

and subsequent carbonyl transposition.

The 5-halo-substituted 6-methyl-β-tetralones of formula I are novel compounds representing important intermediates in the synthesis of pure terutroban. These compounds are accessible from the available starting materials in a straightforward manner.

Process for the preparation of 5-halo-substituted 6-methyl-β-tetralones of the general formula L

wherein X is a halogen atom, such as chlorine, bromine or iodine, wherein the 4- (2-halo-3-methylphenyl) butanoic acid of formula III is: · ·· · · · ·

COOH (III) / in which X is as defined above, in step A, by activating agents such as thionyl chloride or oxalyl chloride, in step B, the acid chlorides of the formula IV obtained are activated,

are cyclized by means of Lewis acids, such as aluminum chloride or tin tetrachloride, obtained in step C by the a-tetralones of the general formula II,

(II) (in which X is as defined above) are reduced by the hydride reducing agents prepared in step D with alcohols of the general formula V,

in which X is as defined above, are dehydrated by means of the acidic reagents obtained in step E by the dihydronaphthalenes of the general formula (V).

in which X is as defined above, are epoxidized with epoxidizing agents, and epoxides of the formula VII produced in step F,

In which X is as defined above, isomerization is by means of isomerizing agents.

A process for the preparation of 5-halo-substituted 6-methyl-3-tetralones of formula I wherein X is a halogen atom such as chlorine, bromine or iodine comprises the following steps:

Step A. Conversion of 4- (2-halo-3-methylphenyl) butanoic acids of formula III in which X is the same as above to the acid chlorides of formula IV in which X is as defined above is carried out with activating agents selected from from a series of inorganic or organic acid halides including thionyl chloride or oxalyl chloride. The process is carried out without a solvent or in the presence of an inert solvent such as toluene or dichloromethane. The reaction is preferably carried out in the presence of a catalytic amount of dimethylformamide.

According to a preferred embodiment, the reaction product is not isolated but is used in the crude state in the next step.

Step B. The cyclization of Friedel and Crafts activated acid derivatives of formula IV, in which X and Y are as defined above, to the acetetralones of formula II in which X is the same as above, is carried out using Lewis acids such as e.g. aluminum chloride or tin tetrachloride. The process is carried out in an inert organic solvent such as dichloromethane or dichloroethane.

Step C. The reduction of α-tetralones of formula II in which X is the same as above to the alcohols of formula V in which X is as defined above is carried out with hydride reducing agents, preferably alkali metal borohydrides, e.g. sodium borohydride.

According to a preferred embodiment, the reaction product is not isolated but is used in the crude state in the next step.

Step D. The alcohols of formula V in which X is as defined above are dehydrated to the dihydronaphthalenes of formula VI with acidic agents selected from a number of inorganic acids or organic sulfonic acids or silicates such as sulfuric acid, acid

methanesulfonic acid, p-toluenesulfonic acid or montmoronite K10. These agents are preferably used in catalytic amounts. The process is carried out in inert organic solvents such as toluene or dichloroethane.

Step E. The epoxidation of the dihydronaphthalenes VI, in which X stands for the same as above, to the epoxides VII is effected by means of epoxidizing agents, such as metho-chloroperbenzoic acid or potassium peroxymonosulphate.

According to a preferred embodiment, the reaction product is not isolated but is used in the crude state in the next step.

Step F. Epoxides of formula (VII) in which X and Y are as defined above are isomerized to β-tetralones of formula (I) in which X is the same as above using isomerizing agents selected from a variety of organic sulfonic acids or silicates such as methanesulfonic acid, toluenesulfonic acid or montmorillonite K10. The process is carried out in inert organic solvents such as toluene or dichloroethane.

An important step in the production of β-tetralones of general formula 0

wherein X represents a halogen atom such as chlorine, bromine or iodine is Friedel and Crafts cyclization

wherein X is as defined above, to α-tetralones of formula IU

(ii) _f in which X denotes the same as above, is carried out with Lewis acids such as aluminum chloride or tin tetrachloride. The process is carried out in an inert organic solvent such as dichloromethane or dichloroethane.

• · «

The required acid chlorides of the formula IV, in which X is as defined above, are prepared by reacting 4- (2-halo-3-methylphenyl) butanoic acids of the formula III - (Hi) _from

COOH wherein X is the same as above, with inorganic or organic acid halides selected from the group of thionyl chloride or oxalyl chloride. The process is carried out without a solvent or in the presence of an inert solvent such as toluene or dichloromethane. The reaction is preferably carried out in the presence of a catalytic amount of dimethylformamide.

According to a preferred embodiment, the reaction product is not isolated but is used in the crude state in the next step.

Another important step is the preparation of the dihydronaphthalenes of the general formula (VI).

(vi) _z in which X represents a halogen atom such as chlorine, bromine or iodine, dehydration of alcohols of formula V,

wherein X is as defined above, using acidic agents selected from a number of inorganic acids or organic sulfonic acids or silicates such as sulfuric acid, methanesulfonic acid, toluenesulfonic acid or montmorillonite K10. These agents are preferably used in catalytic amounts. The process is carried out in inert organic solvents such as toluene or dichloroethane.

The alcohols of formula V in which X is as defined above are produced by reducing the α-tetralones of formula ΙΙ _Λ (ii),

O • · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Wherein X denotes the same as above, by means of hydride reducing agents, preferably alkali metal borohydrides, e.g. sodium borohydride.

According to a preferred embodiment, the reaction product is not isolated but is used in the crude state in the next step.

An essential step in the production of β-tetralones of formula L

in which X represents a halogen atom such as chlorine, bromine or iodine, isomerization of the epoxides of the general formula VIL

wherein X is the same as above, with isomerizing agents selected from a number of organic sulfonic acids or silicates such as methanesulfonic acid, toluenesulfonic acid or montmorillonite K10. The process is carried out in inert organic solvents such as toluene or dichloroethane.

The production of epoxides of the formula VII in which X is as defined above is carried out by epoxidation of the dihydronaphthalenes of the formula VI in which X stands for the same as above, with epoxidizing agents such as meta-.alpha.-chloroperbenzoic acid or potassium peroxymonosulfate.

According to a preferred embodiment, the reaction product is not isolated but is used in the crude state in the next step.

The starting 4- (2-halo-3-methylphenyl) butanoic acids of the general formula III in which X represents a halogen atom such as chlorine, bromine or iodine can be prepared by multistep processes using malonate chemistry or preferably by Michael addition of organometallic reagents. for acrylates. This process is illustrated by the synthesis of 4- (2-bromo-3-methylphenyl) butanoic acid of formula IIIa (Formula III: X = Br) in the following Scheme 1:

COOR

NaBrO ₃ / Na ₂ S ₂ O ₅ Cl 2 a ^a = g _r

Scheme 1

4- (2-Halo-3-methylphenyl) butanoic acids of the general formula III

wherein X is bromo or iodo are new and are useful intermediates in the synthesis of terutroban.

Particularly useful is the acid of formula III wherein X is bromine. It is therefore 4- (2-bromo-3-methylphenyl) butanoic acid of the formula IIIa)

5-Halogen-6-methyl-3,4-dihydronaphthalenes of formula VI _Z

in which X represents a halogen atom such as chlorine, bromine or iodine are novel compounds and are important intermediates in the synthesis of terutroban.

A particularly important intermediate is the dihydronaphthalene of formula VI wherein X is bromine. Thus, it is 5-bromo-6-methyl-3,4-dihydronaphthalene of formula VIa

· · · · · · · · · · · · ·

5-Halogen-6-methyl-3,4-dihydronaphthalen-2 (1 H) -one of formula (I) _:

in which X represents a halogen atom such as chlorine, bromine or iodine are novel compounds and are valuable intermediates in the synthesis of terutroban.

A particularly valuable intermediate is the β-tetralone of formula I wherein X is bromine. Thus, it is 5-bromo-6-methyl-3,4-dihydronaphthalen-2 (17H) -one of formula Ia #

The following examples illustrate but do not limit the generality of the inventive process.

Examples

Example 1

a) Preparation of 5-bromo-6-methyl-3,4-dihydronaphthalen-1 (2Z7) -one of Formula IIa (Formula II, X = Br)

The flask was charged with an acid of formula IIIa (formula III, X = Br; 59.82 g, 0.233 mol), dissolved in toluene (195 mL) with stirring and thionyl chloride (31 mL, 0.507 mol) was added under inert. The reaction mixture was heated (bath temperature 85 ° C), stirred for 1 h, then 6 ml of thionyl chloride was added and the mixture was refluxed for 3 h (bath temperature 120 ° C). After cooling, the solvent was evaporated on an RVO (at 50 ° C in a bath). The crude chloride residue of formula IVa (formula IV: X = Br) was dissolved in DCM (300 ml) and cooled to 0 ° C. Aluminum chloride (36.37 g, 0.273 mol) was added gradually in about 6g portions with cooling, and the mixture was stirred under inert overnight with slow spontaneous heating to rt. To the reaction mixture was slowly added dropwise 15% hydrochloric acid (39 mL) with stirring and cooling in a water bath; the mixture foams, heats, and a solid precipitates. Water is then added and the organic layer is separated. The aqueous layer was shaken with DCM (1 x 100 mL; 2 → 50 mL) and the combined organics were washed with water. Add desiccant (MgSO4) and add a desiccant. carboraffin, stirred for 0.5 h, and filtered through diatomaceous earth. The filtrate is concentrated to a

RVO. 54.61 g, i.e. 98.17 phyo, of α-tetralone of formula IIa (formula II: X = Br) are obtained, with a purity by HPLC of 89.6%, as a brown oil which gradually crystallizes.

H NMR (250 MHz, CDC1 ₃₎ δ 7 92 (d, J = 7.9 Hz, 1H, Ar), 7-21 (d, J = 7.9 Hz, 1H, Ar), ' «Z

3.03 (t, 2H, J = 6.2 Hz, CH? Ar), 2.68-2.55 (m, 2H, CH _CO), 2.47 (s, 3H, CH ₃₎ 2 , 24x2.02 (m, 2H, 7.6 Hz, 2H, CH ₂ CH ₂ CO);

¹³ C NMR (62.895 MHz, CDCl ₃ ) δ 197.34, 144.36, 143.77, 132.38, 128.74, 127.07, 125.94, 37.93, 30.67, 24.48 , 22.41

b) Preparation of 8-bromo-7-methyl-1,2-dihydronaphthalene of Formula VIa (Formula VI: X = Br)

Add to the flask α-tetralone of formula IIa (formula II: X = Br; 81.45 g, 0.34 mol), stir in ethanol (840 ml), mix in small portions (6 * 8 portions) over 30 minutes. NaBH4 (13.16 g, 0.346 mol, 1.02 equiv) was added and the reaction mixture was stirred at rt for 2 h. Then, 15% hydrochloric acid (77 ml) was added dropwise over 30 min, water (200 ml) was added and the RVO was evaporated from ethanol. Water (600 ml) was added to the condenser, and the product was taken up in toluene (1 (x 500 ml; x x 400 ml; x x 300 ml). The combined organics were washed with brine (200 ml), dried over MgSO4 and evaporated to a residue. RVO.

-bromo-6-methyl-1,2,3,4-tetrahydronaphthalen-1-one 1 H NMR (250 MHz, CDCl ₃ ) δ 7.31 (d, 1H, J = 7.8 Hz); 7.11 (m, 1H); 4.76 (m, 1H, OH);

2.88 (m, 1H), 2.67 (m, 1H), 2.40 (s, 3H), 1.75 * 2.08 (m, 4H), 1.63 (m, 1H) ¹³ C NMR (62.895 MHz, CDCl ₃ ) δ 138.5, 137.8, 136.9, 128.3, 127.9, 127.3, 68.2, 31.5, 30.9, 23.8, 18 , 6

The residue was dissolved in dry toluene (840 mL), p-toluenesulfonic acid (PTSA; 5.7 g, 30 mmol, 0.088 equiv.) Was added and stirred under inert boiling for 1 h. NaHCO ₃ (340 mL) and brine (340 mL). Let the organic phase dry over MgSO 4 and evaporate to RVO. The product is purified by vacuum distillation: mp 78 * 84 ° C / 132 Pa. 55.64 g of a colorless to yellowish liquid are obtained; The yield of compound VIa (formula VI: X = Br) is 73.2%, HPLC purity 96.6%.

1 H NMR (250 MHz, CDCl ₃ ) δ 9.85 (bs, 1H, OH), 7.22 * 6.91 (m, 3H, aromatic H), 2.80 (t, 2H, J = 7.6) Hz, CH ₂ -Ar), 2.46-2.29 (m, 2H, CH ₂ COOH 1 2.40 (s, 3H, CH ₃ ), 1.95 (quintet, 2H, J = 7.6 Hz) , CH ₂ CH ₂ COOH);

¹³ C NMR (62.895 MHz, CDCl ₃ ) δ 179.32, 141.02, 138.65, 128.66, 127.77, 127.10, 126.79, 36.01, 33.78, 24.84 , 24.01.

c) Preparation of 5-bromo-6-methyl-3,4-dihydronaphthalen-2 (17H) -one of Formula Ia (Formula I, X = Br)

To a solution of 32.0 g (143 mmol) of 5-bromo-6-methyl-3,4-dihydronaphthalene of Formula VIa in ethyl acetate (675 mL) was added water (615 mL), NaHCO 3 (55.62 g), and acetone (108 mL). ml). A solution of oxone (121.8 g) in 820 ml of water was then added dropwise with stirring over 60 minutes. The reaction is slightly thermally colored, the temperature rises from 22 ° C to 26 ° C. After the dropwise addition, the reaction mixture was stirred for 90 min, and the progress of the reaction was monitored by HPLC. Then the phases were separated, and the aqueous layer was shaken with ethyl acetate (^4 400 mL). The combined organic layers were shaken with brine (200 mL), dried *

MgSO 4 and evaporated to RVO.

The residue was stirred under an inert atmosphere in toluene (1540 mL), Montmorillonite K10 (1.54 g) was added, and the reaction mixture was stirred for 60 min at a bath temperature of 60 ° C (HPLC control). The mixture was filtered through diatomaceous earth and shaken with 9% NaHCO 3 solution (400 mL), water (300 mL) and brine (250 mL). The resulting solution was dried over MgSO 4 and evaporated to RVO. The product (33.78 g) was purified by silica gel column chromatography (350 g) in petroleum ether: ethyl acetate (9: 1). Yield 21.33 g (62.2%) of the compound of formula Ia (formula I: X = Br), HPLC 97.8%.

1 H-NMR (250 MHz, CDCl ₃ ): 7.11 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 3.57 (s, 2H), 3.28 (t, J = 6.7 Hz, 2H), 2.55 (t, J = 6.7 Hz, 2H), 2.42 (s, 3H).

^I3 C NMR (62.895 MHz, CDC1 _3): 210.0, 137.0, 136.5, 132.5, 129.0, 126.9, 126.4, 44.6, 37,8,28, 8,23,8.

HR-MS: calcd for C11H12OBr [M-H] @ +, 239.0072 and 241.0051, found 239.0064 and 241.0043.

IR (neat, v (cm &^lt; -1 & gt ^; )): 3408 (w), 2981, 2941, 2890 (w), 1915 (w), 1711 (w), 1597, 1557 (w), 1472, 1435, 1400, 1308 , 1186, 1130, 1025.940, 865.835, 821.813.778.750.

Example 2 Preparation of 5-bromo-6-methyl-3,4-dihydronaphthalen-2 (1 H) -one of Formula Ia (Formula I: X = Br)

The procedure of Example 1c is followed, but the β-tetralone of formula Ia (compound of formula I: X = Br) is not isolated. The toluene solution is analyzed (average product content Ia about 70%) and concentrated to about 1/5 of the volume on the RVO. The toluene solution is stored in a refrigerator under argon and used directly in the next step in the production of terutroban.

Example 3

Preparation of 4- (2-bromo-3-methylphenyl) butanoic acid of formula IIIa (Formula III: X = Br)

To flask A was charged with lithium chloride (13.08 g, 0.308 mmol) and dried in vacuo at 400 ° C for 10 min. Zinc (22.0 g, 0.336 mol), dry tetrahydrofuran (60 mL) and 1,2-dibromoethane (1.1 mL - exothermic reaction) are then added under an inert argon atmosphere. The mixture was stirred for 5 * 10 min, then trimethylsilyl chloride (TMSCl; 0.6 mL) was added and further stirred for 5 and 10 min. To the mixture was added dropwise a solution of the bromide of formula IXa (Formula IX: X = Br; 53.2 g, 0.2 mol) in tht dry THF (70 mL) over 30 * 50 min with cooling in a 5x10 ° C water bath ( exothermic reactions).

The reaction mixture was stirred for 2 hcd and then allowed to settle.

Another flask was charged again with LiCl (21.3 g, 0.502 mol), dried under vacuum at 400 ° C for 10 min, then CuCN (22.8 g, 0.254 mol) and dry THF (22.8 g, 0.254 mol) were added under argon. 220 ml). The mixture was stirred at room temperature (rt) to give a green solution, which was cooled to -35 to -40 ° C, and then the zinc reagent prepared above was pushed through the cannula. The residue in flask A was washed with THF (35 mL) and the solution was again pushed to the reaction mixture.

After stirring for 10 minutes, ethyl acrylate (22 g, 0.220 mol) and TMSCl (60 mL, 0473 mol) were added to the resulting mixture at -35 ° C. The reaction mixture was stirred for 15 minutes, the cooling was turned off, and the stirred mixture was allowed to warm to rt overnight. Quench the reaction by adding a mixture of saturated ammonium chloride solution (200 mL) and ammonia (25% aqueous solution, 100 mL) and stir for 1 h. Filter the precipitate and wash with THF (100 mL) and water (100 mL). The separated aqueous layer was washed with THF (2x200 mL) and the combined organic layers were shaken with brine (100 mL), dried (MgSO 4) and evaporated to an RVO. The crude ethyl ester of formula X (R = Et) was obtained as a thick oil.

To the residue of ethyl ester X was added aqueous-alcoholic potassium hydroxide solution (from 50 g

KOH, water (170 mL) and ethanol (150 mL)), and the mixture is refluxed for 3 h. Ethanol is distilled off to

RVO, add water (400 mL), and shake with dichloromethane (DCM; ^ 200 mL). This DCM shake contains impurities from the previous stage. The aqueous layer was slowly acidified with conc. acid in hydrochloric acid (70 ml; white precipitate formed) and then shaken with DCM (2x 200 ml, 1x

100 ml). Combine the organic portions, dry over MgSO 4 and evaporate the solvent to RVO. Get u

30.77 g (59.3% of theory) of the acid of formula IIIa (Formula III: X = Br) as a yellow solid, HPLC 89.7%.

^Λ 1 H NMR (250 MHz, CDCl ₃ ) δ 9.85 (bs, 1H, OH), 7.22 * 6.91 (m, 3H, aromatic H), 2.80 (t,

0 £ ^f

2H, J = 76 Hz, CH 2 _? -Ar). 2.46 * 2? (M, 2H, CH 7 COOH). 2.40 (s, 3H, CH ₃ ), 1.95 (quintet, 2H, J = 7.6 Hz, CH ₂ CH ₂ COOH);

¹³ C NMR _(62? 895 MHz, CDC13) δ 179.32, 141.02, 138.65, 128.66, 127.77, 127.10, 126.79, 36.01, 33.78, 24, 84, 24.01.

• · · · · · · · · · · · · · ·

Example 4

Preparation of 2-bromo-3-methylbenzyl bromide of Formula IXa (Formula IX: X = Br)

To the flask was charged 114.0 g (0.616 mol) of 2-bromo-1,3-dimethylbenzene of Formula VIIIa (Formula VIII: X = Br), chloroform (800 mL) was added, and the resulting solution was added under an inert nitrogen atmosphere. NBS (108 g, 0.607 mol). Dibenzoyl peroxide (1.55 g, 6.4 mmol; a total of 5 portions over 20 minutes) was then added portionwise with stirring. The mixture was then heated to reflux (bath temperature 70 ° C) and stirred at this temperature for 24-26 hours. After cooling, the reaction mixture was filtered through a pad of silica gel (30 g) on a frit, washed with chloroform (200 mL) and hexane (200 mL). The solvents were then evaporated on a rotary evaporator (RVO) and evaporator

Drawbar.

is vacuum distilled (at 132 Pa). A fraction with a boiling point of 92 * 102 ° C was collected. 106.04 g, i.e. 64.71%, of a compound of formula IXa (Formula IX: X = Br) is obtained as a colorless, strongly irritating liquid. GC purity above 90%. 1 H NMR (250 MHz, CDCl ₃ ) δ 7.32 * 7.22 (m, 1H, arom. H), 7.22 * 7.13 (m, 2H, arom. H), 4.64 ( s, 2H, _CH2), 2.42 (s, 3H, CH _3);

¹³ C NMR (62.895 MHz, CDCl 3) δ 139.40, 137.31, 130.94, 128.66, 127.23, 127.01, 34.58, 74.73.

Example 5

Preparation of 3- (2-bromo-3-methylphenyl) propanoic acid of formula 10

Sodium (4.65 g, 162 mmol, 1.25 eq) was carefully added in small portions to the stirred abs. EtOH (150 mL), stirred 1 h at RT under Ar until dissolution, heated to 50 ° C, then added diethyl malonate (32 mL, 1.3 eq, 211 mmol), stirred for 20 min, then dropwise addition of bromide IXa solution (42, 7 g, 162 mmol) over 25 min, reflux 16 h, cooled to RT, evaporated to dryness, plus water (150 mL), pH adjusted to give * 2 (My-5 mL conc. HCl), orange suspension washed with DCM ( 3 x 50 mL), washed with water (20 mL), brine (20 mL) and dried over MgSO 4. Filtration, RVP, yielded a yellow oil (60.6 g) added EtOH (100 mL) and 4M NaOH (100 g in 600 mL H ₂ O), reflux 5 h, t,

EtOH-H ₂ O distilled off (give »160 ml), cooled to RT, precipitated crystals (reaction product)

(ethoxide with benzyl bromide) removed, the filtrate cooled to 0 ° C with acidified with conc. HCl (300 ml), thick white slurry heated to reflex 22 h, cooled, DCM extraction (3 x 100 ml), organics washed with water (100 ml), brine (100 ml), dried over Na 2 SO ₄ , filtration and RVP,

29.5 g of solid are obtained, recrystallization from toluene (47 ml), 18.7 g (47ξ / ο) crystals,

mp 117/119 ° C. ^! 1 H-NMR (CDCl ₃ ): 7.12 (m, 3H), 3.11 (t, 7.5 Hz), 2.71 (t, 7.5 Hz), 2.42 (s, 3H) ,

Example 6

Preparation of 5-bromo-6-methyl-3,4-dihydronaphthalen-2 (1H) -one of Formula Ia

3- (2-Bromo-3-methylphenyl) propanoic acid (7.0 g, 28.79 mmol) was dissolved in thionyl chloride (35 mL, 0.49 mol, 17 eq.) With reflux exclusion of moisture (3 h), The thionyl chloride was distilled off at ca 40 ° C under reduced pressure (water pump), the crude chloride was dissolved in Ether (20 mL) and evaporated to RVP (3x). Meanwhile, a solution of diazomethane in ether (200 mL melt) (without EtOH) was prepared from 16.8 g (78.42 mmol, 2.7 eq) of Diazald ™ by the procedure described (Aldrich, using methylcarbitol), to the cooled ( A -40 ° C) solution was added dropwise under stirring to an Ar solution of acyl chloride in ether (50 mL) over 15 min), allowed to warm to RT overnight. The ether was distilled off under reduced pressure (water pump, using an ice-cooled AcOH freezer), a yellow oily residue purified by silica gel chromatography (Hex: EtOAc 80:20) to give a diazoketone (6.9 g, 90%) yellow oil.

1 H-NMR (CDCl 3): 7.10 (m, 3H), 5.21 (bs, 1H), 3.10 (t, 7.5Hz, 2H), 2.65 (bt, 7.5Hz, 2H), 2.42 (s, 3H).

-Dissolved in DCM (200 ml) and added dropwise under Ar to a refluxing solution of Rh 2 (OAc) ₄ (0.084 g, 0.7 / ¹ ¼) in dichloromethane (1500 ml) over 2 h, reflux for 1 h, cooled, washed water (100 mL), 10% NaHCO ₃ (100 mL), brine (100 mL), Na 2 SO ₄ , filtration, concentrated to RVP to * 500 mL, under Ar dropwise addition of TFA (3 mL), stirred at RT 1h, TLC finished, washed with water (100 mL), 10% NaHCl 3 (100 mL), washed with water (100 mL) and brine (100 mL), Na ₂ SO ₄ , filtration, RVP, overnight in the freezer, chromatography (S1O2, Hex: EtOAc 90:10) obtained beta tetralone υ oil crystallizes quickly (4.77 g, 77% from diazoketone), HPLC 94.1% • ·

1 H-NMR (CDCl 3): 7.11 (d, 7.8 Hz, 1H), 6.97 (d, 7.8 Hz, 1H), 3.57 (s, 2H), 3.28 (t (6.7Hz, 2H),

2.55 (t, 6.7 Hz, 2H); 2.42 (s, 3H).

¹³ C-NMR (CDCl 3): 210.0, 137.0, 136.5, 132.5, 129.0, 126.9, 126.4, 44.6, 37.8, 28.8, 23.8.

GC-MS: MW 238/239, HR-MS: calcd. For C11H41Or [M-H] + 239.0072 and 241.0051, found 239.0064 and 241.0043.

IR (neat, wavelength (cm ^-1 )): 3408 (w), 2981, 2941, 2890 (w), 1915 (w), 1711 (w), 1597, 1557 (w), 1472, 1435, 1400, 1308 1186, 1130, 1025, 940, 865, 835, 821, 813, 778.

Claims (12)

1) A process for the preparation of 5-halo-substituted 6-methyl-p-tetralones of the general formula 7 wherein X is a halogen atom such as chlorine, bromine or iodine, characterized in that the acids are 4- (2-halo-3-methylphenyl) butane of the general formula III < in which X is as defined above, in step A, they are activated by activating agents, in step B, the acid chlorides of the formula IV are obtained, in which X is as defined above, cyclized by Lewis acids, in step C the α-tetralones In step D, the alcohols of formula V in which X is the same as above are dehydrated with acid reagents in a solvent, in step E the dihydronaphthalenes of the formula I are obtained. VI ». in which X is as defined above, are epoxidized with epoxidizing agents, and in step F the epoxides of formula VII 'are prepared. wherein X is as defined above, is isomerized with isomerizing agents in a solvent. 2. The process according to claim 1, wherein the activating agent in step A is thionyl chloride or oxalyl chloride. 3. The process according to claim 1, wherein the Lewis acid in step B is aluminum chloride or tin (II) chloride. The process according to claim 1, wherein the hydride reducing agent in step C is an alkali metal borohydride. 5. The process of claim 1 wherein the acidic dehydrating agent in Step D is selected from the group consisting of sulfuric acid, methanesulfonic acid, toluenesulfonic acid, or montmorillonite K10. 6. The process of claim 1 wherein the solvent in Step D is toluene or dichloroethane. 7. The process of claim 1 wherein in step E the epoxidizing agent is selected from the group consisting of m-chloroperbenzoic acid, peracetic acid or potassium peroxymonosulfate. 8. The process of claim 1 wherein in step F the isomerizing agent is selected from methanesulfonic acid, toluenesulfonic acid, or montmorillonite K10. 9. The process of claim 1 wherein the solvent in Step F is toluene or dichloroethane. 10) 4- (2-Bromo-3-methylphenyl) butanoic acid of formula IIIa (IIIa). COOH 11) 5-Bromo-6-methyl-3,4-dihydronaphthalene of formula vK (VIa). 12) 5-Bromo-6-methyl-3,4-dihydronaphthalen-2 (1H) -one of formula (I '). (la).