FI75336C - ANVAENDNING AV -HYDROXYKETONACETALER. - Google Patents

Description

x 75336 (Use of Χ-hydroxyketone acetals

The invention relates to the use of CX-hydroxyketone acetals of the formula VI-1

OR3 OH

3 I I 1

Ar-- C-CH-VI-1 10 1 4

OR

3 wherein Ar is 6-methoxy-2-naphthyl, 4-isobutylphenyl, 4-lower alkoxyphenyl, 4-difluoromethoxyphenyl-1,2-thienyl, 4- (1-oxo-2-isoinodolinyl) phenyl, 4-biphenyl or 4 - (tert-butyl) phenyl, and R 3 is hydrogen or a saturated aliphatic group, or Ar 3 and R 3 form a fused ring together with the carbon atoms to which they are attached, and R and R are independently alkyl groups or form alkyl groups. together in the preparation of an alkylene group, alkanoic acids substituted by an aromatic group in the Qt position and their esters of formula 1-2

25 I

Ar 3 -CH-COOR 2 1-2 3 1 3 wherein Ar and R are as defined above or Ar and R 3 may together form a fused ring with the 2 30 carbon atoms to which they are attached and R is hydrogen, alkyl or hydroxyalkyl, wherein The compound of VI-1 is reacted with a compound of formula 35 R 5 -SO 2 -Hal or (R 5 SO 2) wherein Hal is halogen and R 3 is lower alkyl, lower 2,75336 haloalkyl, phenyl, lower alkylphenyl, halophenyl or d- or 1-camphoryl, and the resulting Ct-sulfonyloxyketone acetal of formula II-2 5 3 5

OR 0SO-R

3 I I x

Ar - C-CH-R II-2 OR4 3 13 4 5 10 wherein Ar, R, R, R and R are as defined above, are hydrolysed in an inert solvent at a temperature of 0 to 250 ° C, preferably 50 to 180 ° C , or treated with a nitrogen affinity agent such as iodotrialkylsilane11a, trialkylsilylperfluoroalkanesulfonate or Lewis acid.

Many compounds of formula I are commercially valuable. For example, CL- (4-isobutylphenyl) propionic acid corresponding to a compound of formula I, 1 2

wherein Ar is 4-isobutylphenyl, R is methyl and R

20 is hydrogen, known as "Ibuprofen", which is an anti-inflammatory drug compound. CL- (6-methoxy-2-naphthyl) propionic acid corresponding to a compound of formula I, 1 2

wherein Ar is 6-methoxy-2-naphthyl, R is methyl and R

is hydrogen, known as "Naproxen". CL (4-difluoro-

25 methoxyphenyl) isovaleric acid corresponding to formula I.

wherein Ar is 4-difluoromethoxyphenyl-12, R is isopropyl and R is hydrogen is very effective as the acid moiety of pyrethroid insecticides.

To date, many methods have been known for the preparation of GL-gaseous aromatic-substituted alkanoic acids. These are described in outline, with reference to the preparation of O- (4-isobutylphenyl) propionic acid (Ibuprofen).

Il 3 75336 1) A process in which a 4-isobutylphenylacetic acid ester prepared in two steps from 4-isobutylacetophenone is reacted with an alkyl carbonate in the presence of a base to form the corresponding malonic ester, methylated with methyl iodide, methylated with methyl iodide, hydrogenated then the product thermally to give the desired propionic acid (GB 971,700).

2) A process for converting 4-isobutylaceto-10-phenone to the corresponding hydantoin with potassium cyanide and ammonium carbonate, hydrolyzing hydantoin to the X-amino acid, alkylating it to a dialkylamino compound, reducing this to C 1 - (4-isobutylphenyl-1-propyl) -propyl 192).

3) A process in which Darzen is reacted with 4-isobutylacetophenol and monochloroacetic acid to form the corresponding epoxycarboxylic ester, the ester is hydrolyzed, the hydrolyzed product is decarboxylated (X- (4-isobutylphenyl) propionaldehyde to 1-propionaldehyde and oxidized ).

4) A process for carrying out a condensation reaction between 4-isobutylbenzaldehyde and formaldehyde mercaptal S-oxide to form ketene mercaptal S-25 oxide by reacting it with thionyl chloride to form Q 1 -chlorokethene mercaptal, this esterifies 4-Isobutylphenyl) -1-alkylthioacetic acid ester, which is methylated, hydrolyzed and desulfurized by reduction, respectively, to give the desired propionic acid (U.S. Patent 4,242,519).

Methods (1) and (4) involve many reaction steps which are not preferred on a technical scale. Method (2) is disadvantageous in this respect because sii-35 involves a step of using a toxic compound such as potassium cyanide.

4,75336

Methods (1) and (3) are economically disadvantageous because the ethoxycarbonyl group initially attached is finally removed in the decarboxylation of the final step.

5 The main application describes the method in the Oi position

for the preparation of aromatic-substituted alkanoic acids and their esters of formula I

R1 • 2

10 Ar-CH-COOR I

wherein Ar is phenyl; 4-X-phenyl, wherein X is halogen, lower alkyl, lower alkoxy, lower haloalkoxy, phenylacetamido or 1-oxo-2-isoindolinyl; 2-thienyl or 6-methoxy-2-naphthyl; and R 1 is hydrogen or a saturated aliphatic group, or Ar and R 1 may together form a fused ring with the carbon atom to which they 2 are attached; and R is hydrogen, alkyl or hydroxyalkyl, wherein d-sulfonyloxyketone acetal of formula II-c

OR 0S0 - R

I I 2 1

Ar - C - CH-R II

I 4

OR

1 3 4

25 wherein Ar and R are as defined above, R and R

are independently an alkyl group or together form an alkylene group; R is lower alkyl, lower haloalkyl, phenyl, lower alkylphenyl, halophenyl or d- or 1-camphoryl, hydrolysed in an inert solvent at a temperature of 0 to 250 ° C, preferably 50 to 180 ° C, or treated with an oxygen affinity an agent such as iodotrialkylsilane, trialylsilyl hyperfluoroalkanesulfonate or Lewis acid.

The term "aromatic group" is to be understood in its broadest sense and means a cyclic compound having aromaticity. Aromaticity refers to the phenomenon in which the ring is stabilized due to the de-localization of JT electrons. In general, a cyclic compound having 5,75336 (4n + 2) conjugated 'ίΓ electrons is stable and exhibits aromaticity. Thus, the term aromatic group as used herein refers to a group of compounds having (4n + 2) conjugated 5L-electrons in the main ring. This group can be roughly classified into aryl groups having at least one optional substituent and heteroaromatic groups having at least one optional substituent; these groups are described in detail below.

The term "saturated aliphatic group" means a straight, branched or cyclic saturated hydrocarbon chain generally having 1 to 10, preferably 1 to 6, carbon atoms. Examples of such saturated aliphatic groups are straight or branched groups having 1 to 6 carbon atoms, especially lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n- pentyl, isoamyl and n-hexyl; and cyclic alkyl groups having 3 to 10 carbon atoms, especially cyclic alkyl groups having 3 to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

The terms "alkyl group" and "alkylene group" may mean straight or branched chain hydrocarbons, and alkylene groups are preferably lower alkene groups such as ethylene, propylene, butylene, trimethylene or tetramethylene.

The term "short chain" means that the group or compound has up to 6, preferably up to 4 carbon atoms.

Compounds of formula VI-1 may be synthesized from da haloketones of formula V-1

O X

3 III!

Ar -C-CH-R Vl 35 3 1 wherein X is a halogen atom and Ar and R are as defined in formula VI-1 above, and compounds of formula VI-1 can be converted to compounds of formula II-2 according to the following reaction scheme: R5 -SO, -Hal, c

3 * OR OSO, -R

O X OR OH - I I 2, Il I 1 p3nH, I! 1 or <RS02> 2 ° Ar1-C-CH-R1

Ar - C-CH-R - 55 »Ar —C-CH RA -► i \ 4 ^ 4 OR2

\ f ° R

\ / (VI-1) (II-2) <X U \ R1OM j r2om \ f / 3 1 1

Ar —C-CH-R

(VII-1)

In the above reaction scheme, M is an alkali metal and Hal is a halogen atom, especially a chlorine atom, and Ar, R, R, R f, R and X are groups as defined above.

A compound of formula X-1 can be readily prepared by administering a compound of formula VIII

X

20 |

R1-CH-COCl VIII

wherein R and X are groups as defined above, react in a Crafts reaction with a compound of formula IX

Ar-H IX

wherein Ar is a group as defined above, or by halogenating in a known manner a compound of formula X-10

30 II

Ar1-C-CH2-R1 X-11 wherein Ar and R are as defined above.

2

The reaction steps in the reaction scheme are described in detail below.

7 75336

Step (VI) - ^ (VI-1) This reaction step is formed between the reaction between an alkali metal alkali-3 oxide (R OM) and a compound of formula VI in the presence of the corresponding alcohol (R OH) to form a compound of formula VI-1. <2-hydroxyketone acetal. In the 3 4 compound of formula VI-1 prepared in this reaction step, R and R are similar groups. Sodium alkoxides and potassium alkoxides can be used as alkali metal alkoxides. Sodium) alkoxides are preferred because of their low cost. The amount of the alkali metal oxide is usually at least 1 mole per mole of the compound of the formula V-1, and the reaction can be carried out rapidly if used in amounts of 1.5 to 3 moles per the mole of the compound of the formula V-1. The amount of alcohol present may be at least one mole per mole of the compound of formula V-1. It is preferable to use an excess of alcohol, in which case it also acts as a solvent. It is also possible to add an aprotic solvent such as di-ethyl ether, tetrahydrofuran, dimethylformamide or 1,2-dimethoxyethane which does not participate in the reaction. The reaction proceeds calmly at temperatures of -20 to about 100 ° C. To simplify the process, the reaction is preferably carried out at a temperature between room temperature and 60 ° C.

According to another embodiment, this reaction step can be performed by reacting a compound of formula VI with an alkali metal alkoxide (R OM) in an aprotic solvent such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane to form an epoxide product of formula VII-1, and giving the compound. react this product with alcohol (R OH) in the presence of a catalytic amount of alkali metal alkoxide (R OM) to give β-hydroxyketone acetal VI-1 35 (see Examples 8 and 9). This method can also be used to prepare a compound of formula VI-1 wherein R and R are different groups.

75336

The reaction between the compound of the formula V-1 and the alkali metal alkoxide (R 1 OM) can usually be carried out at a temperature of 0 to 60 ° C using 1 to 3 moles of the alkali metal alkoxide per one mole of the compound of the formula V-1. The reaction between a compound of formula VII-1 and al-4 (R OH) can usually be carried out at a temperature between about 0 ° C and 100 ° C using at least one mole of alcohol per mole of compound of formula VII-1. It is preferred to use an excess of alcohol, in which case it also acts as a solvent.

According to a further embodiment of this reaction step, a QS haloketone of formula V-1 is reacted with a monohydric salt of a dihydric alcohol and an alkali metal in the presence of a dihydric alcohol such as ethylene glycol, propylene glycol or 1,3-propyldiol to give OC-hydroxides of formula VI-1. By this method 3 4 4 of a product of formula VI-1 are obtained in which R and R together form an alkene group such as ethylene, propylene or trimethylene (see Example 111).

The reaction can generally be carried out at 0 to 100 ° C using at least one mole, preferably 1.5 to 3 moles, of the monoalkali metal salt of the dihydric alcohol at least 0.5, preferably 2 to 10, moles per dihydric alcohol. An aprotic solvent such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane which does not participate in the reaction may be added to the reaction.

Of the compounds of formula 3 VI-1 obtained from the above reaction step, only the compound in which Ar is 34 p-methoxyphenyl and R and R are both methyl has been described in the literature. Chemical Abstracts, vol. 62 (1965), ss. 5170 ^.

The compound of formula VI-1 can also be prepared by other methods, such as the method of oxidizing 1- (aromatic group) -1-alkoxy-1-alkene of formula XI-1.

OR

3 1 1

Ar -C = CH-Ra XI-1 li 9 75336 3 1 3 wherein Ar, R and R are groups as defined above to form an epoxide compound of formula VII-1, and by preparing from this epoxide compound a Οί- hydroksiketoniasetaali; and a process for reducing a Cfc oxyketone acetal of the formula ~ OR 0 3 1 II 1

Ar —C-CR XII-1

I 4 OR

10 3 13 4 wherein Ar, R, R and R are groups as defined above to form a # -hydroxyketone acetate of formula VI-1.

Step (VI-1) -½ ((II-2) This reaction step, in which the product of formula II-2 is formed, forms an O-sulfonylating compound of formula R -SO 2 - Hal or (R SO 2 - 2 ° to the reaction of the Cfc hydroxyketone acetal of formula VI-1 obtained in the above reaction step Examples of O-sulfonylating compounds include aromatic-substituted sulfonyl halides such as benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-bromine sulfone, p-bromine -nitrobenzenesulfonyl chloride and naphthalenesulfonyl chloride, and alkanesulfonyl halides or alkanesulfonic anhydrides such as methanesulfonic anhydride, trifluoromethanesulfonic anhydride, d-10-camphorsulfonyl chloride and 1-10-camphorsulfonide

The reaction is preferably carried out under neutral or basic conditions and therefore the reaction can be carried out successfully when at least one mole of a tertiary amine such as triethylamine pyridine or 4-dimethylaminopyridine is present per mole of the compound of formula VI-1. In this way, the reaction can be carried out at a relatively low temperature from about 0 ° C to room temperature. It is also possible to add an aprotic solvent such as methylene chloride or diethyl ether which does not participate in the reaction.

The following examples illustrate the invention.

75336 10

Example 1 9.81 g of p-toluenesulfonyl chloride was dissolved in 10 ml of anhydrous pyridine, and the mixture was stirred at room temperature. A solution of 6.65 g of OC-hydroxypropiophenone dimethyl acetal and 10 ml of anhydrous pyridine was added dropwise to the mixture over 10 minutes, and the mixture was stirred for 48 hours. The reaction mixture was poured into 200 ml of ice water and stirred for two hours. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure over potassium hydroxide to give 10.91 g of Of- (p-toluenesulfonyloxy) propionophenone dimethyl acetal as colorless crystals.

Yield 92%, m.p. 62-63 ° C (from petroleum ether).

IR (KBr): 1360, 1190, 1175, 1090, 1060, 1040, 910, 710 cm -1.

NMR (CDCl 3): 1.07 (3H, d, J = 6 Hz), 2.73 (3H, s), 3.08 (3H, s), 3.15 (3H, s), 4.95 (1H, q, J = 6 Hz), 7.33 (7H, m), 7.77 (2H, d, J = 9 Hz).

Elemental analysis for C 18 H 22 ° 5SL

Calculated: C 61.70 H 6.33 S 9.15% 20 Found: C 61.72 H 6.26 S 9.19%

Example 2 19.0 g of p-isobutylpropionophenone was dissolved in a mixture of 15 ml of anhydrous diethyl ether and 5 ml of anhydrous dioxane, and the mixture was stirred at room temperature. Bromine (17.6 g) was added dropwise over 25 minutes and the mixture was stirred for 2.5 hours. Water (50 ml) was added and the mixture was extracted three times with 20 ml of diethyl ether. The extract was washed with 50 ml of water, dried four times with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 30 ml of hot methanol and cooled to -40 ° C. The precipitate was collected by filtration and washed with cold methanol to give 21.88 g of O (bromo-p-isobutylpropionophenone as colorless crystals).

Yield 81%, m.p. 63-66 ° C.

IR (KBr): 2950, 1680, 1608, 1419, 1260, 1250, 1167, 955, 862 cm-1.

NMR (CDCl 3): δ 0.91 (6H, d, J = 7 Hz), 1.87 (3H, d, J = 7 Hz), 1.8 - 2.2 (1H , m), 2.52 (2H, d, J = 7 Hz), 5.25 (1H, q, J = 7 Hz), 7.22 (2H, d, J = 9 Hz), 7.92 ( 2H, d, J = 9 Hz).

5 Elemental analysis for C

Calculated: C 58.00 H 6.37 Br 29.69%

Found: C 57.80 H 6.27 Br 29.42%

Example 3

Sodium methoxide (1.134 g) was dissolved in 20 ml of anhydrous methanol, and the mixture was stirred at room temperature under an argon atmosphere. A solution of 20 ml of anhydrous methanol and 2.692 g of Ot-bromo-p-isobutylpropionophenone was added dropwise to the solution over 30 minutes. After the addition, 50 ml of water was added to the reaction mixture, and the mixture was extracted with 20 ml of diethyl ether three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate and potassium carbonate, and concentrated under reduced pressure in the presence of a small amount of potassium carbonate to give 2.370 g of GC-hydroxy-p-isobutylpropionophenone dimethyl acetal as a colorless oil. The yield was 94%. For elemental analysis, the compound was purified by column chromatography (florisil; methylene chloride).

IR (neat): 3500, 2950, 1460, 1100, 1050, 980, 850, 800, 740 cm-1.

NMR (CDCl 3): δ 0.91 (6H, d, J = 7 Hz), 0.96 (3H, d, J = 7 Hz), 1.6 - 2.1 (1H, m), 2, 43 (2H, d, J = 7Hz), 2.57 (1H, broad s), 3.20 (3H, s), 3.30 (3H, s), 4.06 (1H, q, J = 7 Hz), 7.08 (2H, d, J = 9 Hz), 7.33 (2H, d, J = 9 Hz).

Elemental analysis for ci5H24 ° 3:

Calculated: C 71.39 H 9.59%

Found: C 71.39 H 9.48%

Example 4 26.84 g of isobutylbenzene and 29.34 g of aluminum chloride were stirred under ice-cooling in 20 ml of carbon disulphide. 40.63 g of Of-chloropropionyl chloride was added dropwise to the mixture over 30 minutes, and the mixture was stirred under ice-cooling for 12 hours. It was stirred for another 30 minutes at room temperature. The reaction mixture was poured into 200 ml of ice water, and 100 ml of concentrated hydrochloric acid was added.

The mixture was extracted with 100 ml of diethyl ether four times.

The extract was washed with 100 ml of water and then four times with 50 ml of saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, the oily residue was dissolved in 40 ml of methanol at elevated temperature, treated with 10 ° C and cooled. a. The precipitated crystals were filtered, washed with chilled methanol to give 17.83 g of of-chloro-p-isobutylpropionophenone as colorless crystals with a melting point of 51-53 ° C.

Yield 40%.

IR (KBr): 2950, 1690, 1608, 1419, 1357, 1266, 1180, 956, 861 cm-1.

NMR (CDCl 3): δ 0.91 (6H, d, J = 7 Hz), 1.71 (3H, d, J = 7 Hz), 1.5 - 2.2 (1H, m), 2.52 (2H, d, J = 7 Hz), 5.20 (1H, q, J = 7 Hz), 7.23 (2H, d, J = 9 Hz), 7.91 (2H, d, 20 J = 9 Hz).

Elemental analysis for C

Calculated: C 69.47 H 7.63 Cl 15.78%

Found: C 69.56 H 7.44 Cl 15.76%

Example 5 Sodium methoxide (0.979 g) was dissolved in 10 ml of anhydrous methanol and the solution was stirred at room temperature under argon. A solution of 10 ml of anhydrous methanol and 2.036 g of C (-chloro-p-isobutylpropionophenone) was added dropwise over 20 minutes, and the mixture was stirred for a further four hours at room temperature, and the usual recovery as in Example 4 gave 2.258 g (95% yield) of OC -hydroxy-p-isobutylpropionophenone dimethyl acetal as a pale yellow oil in 95% yield.

Example 6 In a similar manner to Example 1, N- (p-toluenesulfonyloxy) -p-isobutylpropion-phenonyldimethylacetal was prepared as colorless crystals of β-hydroxy-p-isobutylpropionophenone-dimethyl-acetal.

Il 13 75336

Yield 89%, m.p. 64-65 ° C (from hexane).

IR (KBr): 2960, 1360, 1185, 1090, 1050, 930, 915, 780 cm NMR (CDCl 3): δ 0.88 (6H, d, J = 7 Hz), 1.09 (3H, d, δ J = 7 Hz), 1.5 - 2.1 (1H, m), 2.40 (3H, s), 2.42 (2H, d, J = 7 Hz), 3.07 (3H, s), 3.15 (3H, s), 4.93 (1H, q, J = 7Hz), 6.9-7.4 (6H, m), 7.72 (2H, d, j = 9Hz).

Elemental analysis for C22H30 ° 5S:

Calculated: C 64.99 H 7.44 S 7.89% 10 Found: C 64.78 H 7.26 S 7.93%

Example 7

Methanesulfonyl chloride (2.94 g) was dissolved in 5 ml of anhydrous pyridine, and the mixture was stirred under ice-cooling. A solution of 10 ml of anhydrous pyridine and 3.23 g of Of-hydroxy-p-isobutylpropionophenone dimethyl acetal was added dropwise over 15 minutes. The mixture was stirred for one hour under ice-cooling and at room temperature for 30 minutes. Water (30 ml) was added and the mixture was stirred for one hour. The mixture was extracted with 10 ml of methylene chloride-20 dia three times, dried over anhydrous magnesium sulfate and concentrated in the presence of a small amount of anhydrous potassium carbonate, the oily residue was purified by column chromatography (florisil; methylene-isopropyl-isopropyl) isoxy-25-isoxy) nifenone dimethyl acetal as a colorless oil.

Yield: 79%.

IR (neat). 2960, 1350, 1175, 1095, 1065, 1040, 915 cm-1.

NMR (CDCl 3): δ 0.88 (6H, d, J = 7 Hz), 1.16 (3H, d, 30 J = 7 Hz), 1.6 - 2.1 (1H, m), 2, 44 (2H, d, J = 7Hz), 3.06 (3H, s), 3.18 (3H, s), 3.26 (3H, s), 4.95 (1H, q, J = 7 Hz), 7.10 (2H, d, J = 8 Hz), 7.32 (2H, d, J = 8 Hz).

Elemental analysis for c16H26H5S:

Calculated: C 58.16 H 7.93 S 9.69% 35 Found: C 58.06 H 7.80 S 9.60% 14 75 3 36

Example 8

Sodium methoxide (9.20 g) was suspended in 10 ml of anhydrous diethyl ether, and the mixture was stirred under an argon atmosphere under ice-cooling. A solution of 80 ml of anhydrous diethyl ether and 15.0 g of C 1 -bromo-p-methoxypropionophenone was added dropwise to the solution over 40 minutes. After the addition, the insoluble matter was separated by filtration under a stream of argon. The filtrate was concentrated under reduced pressure to give 7.88 g of 1- (4-methoxyphenyl) -1-methoxy-1,2-epoxypropane as a pink oil.

Yield: 68%.

NMR (CDCl 3): δ 1.00 (3H, d, J = 6 Hz), 3.23 (3H, s), 3.52 (1H, q, J = 6 Hz), 3.82 (3H, s ), 6.92 (2H, d, J = 7Hz), 7.38 (2H, d, J = 7Hz).

Example 9 7.88 g of 1- (4-methoxyphenyl) -1-methoxy-1,2-epoxypropane and 200 mg of sodium methoxide were stirred in 30 ml of anhydrous methanol at room temperature for 15 hours. Water (50 ml) was added to the reaction solution, and the mixture was extracted with 20 ml of diethyl ether three times. The extracts were dried over anhydrous magnesium sulfate and anhydrous magnesium carbonate and concentrated under reduced pressure in the presence of a small amount of potassium carbonate to give 8.26 g of Of-hydroxy-p-methoxypropionophenone dimethyl acetal as a colorless oil. For elemental analysis, this product was purified by column chromatography (florisil-methylene chloride).

Yield 61%.

IR (neat): 3520, 1050 cm NMR (CDCl 3): δ 0.94 (3H, d, J = 7 Hz), 2.35 (1H, 30 d, J = 4 Hz), 3.20 (3H, s), 3.33 (3H, s), 3.78 (3H, s), 4.05 (1H, dq, J = 4 and 7 Hz), 6.18 (2H, d, J = 9 Hz) , 7.35 (2H, d, J = 9Hz).

Elemental analysis for C 20 H 18 O 4:

Calculated: C 63.70 H 8.02% 35 Found: C 63.98 H 8.08% tl is 7 5 3 3 6

Example 10 2.67 g of p-toluenesulfonyl chloride was dissolved in 5 ml of anhydrous pyridine, and the solution was stirred at room temperature. A solution of 5 ml of anhydrous pyridine and 1.58 g of GC-hydroxy-p-methoxypropionophenone dimethyl acetal was added dropwise to the solution over 10 minutes. The mixture was stirred for 72 hours. Ice water (about 20 g) was added and the mixture was extracted with 20 ml of diethyl ether three times. The extracts were washed with 20 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure in the presence of a small amount of anhydrous potassium carbonate to give 2.12 g of Of- (p-toluenesulfonyloxy) -p-methoxypropionophenone dimethyl acetal as a pale yellow oil.

Yield: 80%.

IR (neat): 1600, 1510, 1350, 1245, 1170, 1090, 1055, 1035, 905 cm -1.

NMR (CDCl 3): δ 1.07 (3H, d, J = 7 Hz), 2.40 (3H, s), 3.07 (3H, s), 3.12 (3H, s), 3.75 (3H, s), 4.92 (1H, q, J = 7Hz), 6.7-7.0 (2H, m), 7.1-7.4 (4H, m), 7.73 ( 2H, 20 d, J = 8 Hz).

Example 11

By the same procedure as in Example 2, Qf-bromo-p- (tert-butyl) isovalerophenone was prepared as a colorless liquid from p- (tert-butyl) isovaleranophenone.

Yield: 72%, m.p. 128-140 ° C / 1 torr.

IR (neat): 2960, 1680, 1600 cm -1.

NMR (CDCl 3): δ 1.00 (3H, d, J = 7 Hz), 1.20 (3H, d, J = 7 Hz), 1.35 (9H, s), 2.2 - 2.7 (1H, m), 4.90 (1H, d, J = 9Hz), 7.47 (2H, d, J = 10Hz), 7.90 (2H, d, J = 10Hz). Elemental analysis for ci5H21OBr:

Calculated: C 60.61 H 7.12 Br 26.89%

Found: C 60.71 H 7.11 Br 26.58%

Example 12

Sodium methoxide (1.62 g) was dissolved in 20 ml of 35 anhydrous methanol, and the mixture was stirred at room temperature under an argon atmosphere. To the resulting solution was added a solution of 20 ml of anhydrous methanol and 16 7 5 3 3 6 2.64 g of α-bromo-p- (tert-butyl) isovalerophenone over 15 minutes, and the mixture was stirred for 18 hours at room temperature. Recovery as in Example 3 gave 2.4 g of Of-hydroxy-p- (tert-butyl) isovaleranephenone dimethyl acetal as a pale yellow oil.

Yield 98%.

IR (neat): 2950, 1110, 1040 cm NMR (CDCl 3): δ 0.70 (3H, d, J = 7 Hz), 0.90 (3H, d, J = 7 Hz), 1.32 (9H , s), 1.0-1.6 (1H, m), 2.45 (1H, 10 broad s), 3.22 (3H, s), 3.25 (3H, s), 3.67 ( 1H, d, J = 6 Hz), 7.33 (4H, s).

Example 13

Methanesulfonyl chloride (1.90 g) was dissolved in 5 ml of anhydrous pyridine, and the solution was stirred at room temperature, and 5 ml of anhydrous pyridine and 2.34 g of Of-hydroxy-p- (tert-butyl) were added dropwise over 10 minutes. ) solution of isovalerophenone dimethyl acetal. The mixture was stirred at the same temperature for another 24 hours. Conventional recovery and separation as in Example 20 gave 1.63 g of (X- (methanesulfonyloxy) -p- (tert-butyl) isovaleranephenone dimethyl acetal as a colorless oil (which crystallized on storage at room temperature).

Yield 55%, m.p. 80-86 ° C.

IR (neat). 2960, 1357, 1176, 1060, 955 cm-1.

NMR (CDCl 3): δ 0.70 (3H, d, J = 7 Hz), 0.90 (3H, d, J = 7 Hz), 1.32 (9H, s), 1.4 - 1 .9 (1H, m), 3.17 (3H, s), 3.20 (3H, s), 3.26 (3H, s), 4.76 (1H, d, J = 4 Hz), .37 (4H, s).

Elemental analysis for C 10 H 19 N 2 O 2 S: 30 Calculated: C 60.30 H 8.44 S 8.95%

Found: C 60.07 H 8.23 S 9.07%

Example 14

Benzene (100 ml) was added to a mixture of 7.12 g of Cf-acetoxyacetophenone, 7.44 g of ethylene glycol 35 and 0.200 g of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux. The water formed was removed with a Dean-Stark attached to a reaction vessel.

After 17 hours at reflux, 4.00 g of ethylene glycol were added. The mixture was heated at reflux for a further six hours. The water formed was removed by distillation. After cooling, 30 ml of saturated aqueous sodium carbonate solution and 20 ml of water were added in this order, and the mixture was extracted twice with 30 ml of diethyl ether. The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 7.874 g of a residue. The residue was determined by NMR spectroscopy and gas chromatography to be a mixture of C 1 -acetoxyacetophenone-ethylene acetal and C (hydroxyacetophenone-ethylene acetal).

The mixture was dissolved in 20 ml of methanol, and 0.300 g of potassium carbonate was added to the solution. The mixture was stirred at room temperature for four hours. Water (200 ml) was added, and the precipitated colorless crystals were collected by filtration and dried overnight under reduced pressure over potassium hydroxide to give 4.79 g of GC-hydroxyacetophenone-ethylene acetal.

Yield 67%.

NMR (CDCl 3): δ 2.10 (1H, broad s), 3.70 (2H, broad s), 3.7-4.0 (2H, m), 4.0-4.2 (2H , m), 7.2 - 7.6 (5H, m).

Example 15

Pyridine (5 ml) was added to 0.900 g of Gf-hydroxyaceto-phenone-ethylene acetal, and the mixture was stirred under ice-cooling. To the mixture was added 1.08 g of p-toluenesulfonyl chloride, and the mixture was stirred for two hours under ice-cooling, and then for one hour at room temperature. The reaction mixture was again cooled on ice. Water (10 ml) was added and the mixture was stirred for one hour and extracted with 20 ml of diethyl ether three times. The extracts were washed twice with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.584 g of a crystalline residue. The residue was washed with a small amount of hexane to give 1.330 g of O- (p-toluenesulfonyl-35-oxy) acetophenone ethylene acetal as colorless crystals.

Yield 80%.

δ 75 3 3 6 NMR (CDCl 3): δ 2.40 (3H, s), 3.7-3.9 (2H, m), 3.9-4.1 (2H, m), 4.11 ( 2H, s), 7.1-7.5 (5H, m), 7.55 (2H, d, J = 8Hz).

Example 16 In a similar procedure to Example 15, O (- (p-bromobenzenesulfonyloxy) acetophenone-ethylene acetal was prepared as a colorless kit from Of-hydroxyacetophenone-ethylene acetal.

Yield 86%.

NMR (CDCl 3): 03.7 - 3.9 (2H, m), 3.9 - 4.1 (2H, m), 4.16 (2H, s), 7.2 - 7.5 (5H , m), 7.63 (4H, s).

Example 17

Sodium metal (0.46 g) was dissolved in 10 ml of anhydrous methanol, and the solution was stirred at room temperature. A solution of 10 ml of anhydrous methanol and 2.19 g of 1- (2-thienyl) -2-bromo-1-propanone was added dropwise to the solution over 10 minutes, and the mixture was stirred for another 3.5 hours at room temperature. Conventional recovery as in Example 3 gave 1.900 g of 1- (2-thienyl) -2-hydroxy-20 1-propanone dimethyl acetal as a colorless oil.

Yield 94%.

IR (neat): 3450, 1110, 1055, 980, 855, 710 cm-1.

NMR (CDCl 3): δ 1.05 (3H, d, J = 7 Hz), 2.54 (1H, broad s), 3.26 (3H, s), 3.30 (3H, s), 4, 16 (1H, broad q, 25 J = 7 Hz), 6.9-7.2 (2H, m), 7.2-7.4 (1H, m).

Example 18 0.606 g of 1- (2-thienyl) -2-hydroxy-1-propanone dimethyl acetal was dissolved in 5 ml of pyridine and the solution was stirred under ice-cooling. 0.30 ml of methanesulfonyl chloride was added to the solution together over 30 minutes, and the mixture was stirred for five minutes under ice-cooling, and then for five hours at room temperature. Water (30 ml) was added and the mixture was stirred for 30 minutes at room temperature and extracted with 30 ml of diethyl ether three times. The extracts were washed twice with 10 ml of water, dried over anhydrous magnesium sulfate and anhydrous potassium carbonate, and concentrated under reduced pressure. Residue

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75336 was purified by column chromatography (florisil; methylene chloride to give 0.788 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propanodimethylacetal as a colorless oil.

5 Yield 94%.

IR (neat): 1360, 1180, 1120, 1055, 990, 975, 930, 905, 855, 810, 715, 540, 525 cm-1.

NMR (CDCl 3): δ 1.27 (3H, d, J = 7 Hz), 3.09 (3H, s), 3.27 (6H, s), 5.02 (1H, q, J = 7 Hz) ), 6.9 - 7.1 (2H, m), 7.2 - 7.4 (1H, m).

Elemental analysis for c10H16 ° 5S2:

Calculated: C 42.84 H 5.75 S 22.87%

Found: C 42.64 H 5.64 S 22.90%

Example 19 Benzenesulfonyl chloride (2.01 g) was dissolved in 10 ml of anhydrous pyridine, and the mixture was stirred at room temperature. A solution of 10 ml of anhydrous pyridine and 1.93 g of N, N-hydroxy-p-isobutylpropiophenone dimethyl acetal was added dropwise to the solution over 15 minutes, and the mixture was stirred for 72 hours. By a similar recovery to Example 1, 2.62 g of O (- (benzenesulfonyloxy) -p-isobutylpropiophenone dimethyl acetal were obtained as colorless crystals.

Yield 88%, m.p. 79-82 ° C.

IR (KBr): 2950, 1362, 1195, 1097, 1043, 990, 921, 813, 594 cm -1.

NMR (CDCl 3): δ 0.86 (6H, d, J = 7 Hz), 1.08 (3H, d, J = 7 Hz), 1.6 - 2.1 (1H, m), 2.41 (2H, d, J = 7Hz), 3.02 (3H, s), 3.10 (3H, s), 4.94 (1H, q, J = 7Hz), 7.04 (2H, s) d, J = 9 Hz), 7.19 (2H, d, J = 9 Hz), 7.36 - 7.70 (3H, m), 7.84 - 8.02 (2H, m).

Example 20 1.91 g of p-toluenesulfonyl chloride was dissolved in 10 ml of anhydrous pyridine, and the mixture was stirred at room temperature. A solution of 10 ml of anhydrous pyridine and 1.13 g of Ofc-hydroxypropiophenone diethyl acetal was added dropwise to the solution over 10 minutes, and the mixture was stirred for 75 hours. Conventional recovery and purification by column chromatography (florisil; methylene chloride) gave 1.16 g of O- (p-toluenesulfonyloxy) propiophenone diethyl acetal as a colorless oil.

5 Yield 85%.

IR (neat): 2980, 1360, 1192, 1178, 1087, 1055, 1042, 920 cm-1.

NMR (CDCl 3): δ 0.8-1.3 (9H, m), 2.38 (3H, s), 3.1-3.6 (4H, m), 4.89 (1H, q, J = 7 Hz), 7.1-7.5 (7H, 10 m), 7.80 (2H, d, J = 9 Hz).

Elemental analysis for C20H26 ° 5S:

Calculated: C 63.46 H 6.93 S 8.47%

Found: C 63.54 H 6.90 S 8.35%

Example 21 0.526 g of <X- (p-toluenesulfonyloxy) propiophenone dimethyl acetal and 0.150 g of calcium carbonate were heated at reflux for 72 hours in a mixture of 10 ml of water and methanol (3: 7 by weight). Water (10 ml) was added and the mixture was extracted with 10 ml of diethyl ether three times.

The extracts were washed with 10 ml of water and dried over anhydrous magnesium sulfate. The product was quantitatively analyzed by gas chromatography (using an internal standard) and found to contain 0.162 g of methyl OC phenylpropanoate. Yield 66%.

Example 22 1.75 g of O - (- (p-toluenesulfonyloxy) propiophenone dimethyl acetal and 0.500 g of calcium carbonate were heated at reflux for 72 hours in a mixture of 33 ml of honey and methanol (3: 7 by weight). Water (50 ml) and the mixture was extracted with 30 ml of diethyl ether three times.

The extracts were washed with 30 ml of water and concentrated in vacuo to about 5 ml. To the residue were added methanol (12 ml), 5 ml of water and 7 ml of 10% aqueous potassium hydroxide solution, and the mixture was heated under reflux for 5 hours. 35 water (30 ml) were added and the mixture was washed with 20 ml of diethyl ether five times. The pH of the aqueous phase was adjusted to 1 with concentrated hydrochloric acid and extracted with 20 ml of diethyl ether.

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75336 21 four times. The extracts were washed with 20 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.358 g of Of-phenylpropionic acid as a colorless oil. Yield 48%. The IR and NMR spectral values of this product were exactly the same as those of the reference substance.

Examples 23-35 0.526 g of Of- (p-toluenesulfonyloxy) propiophenone dimethyl acetal and an equimolar amount of each of the bases listed in Table 1 were heated in an oil bath of 10 ml in 10 ml of the various solvents listed in Table 1. Water (10 ml) was added and the mixture was extracted with 10 ml of diethyl ether three times. The extracts were washed with 10 ml of water and dried over anhydrous magnesium sulfate. The product was analyzed for methyl O-phenylpropionate by gas chromatography in the same manner as in Example 21. The results are shown in Table 1.

22 7 5 3 3 6

table 1

Eg Solvent (mixed Base-Hau- Reaction- Methyl-O (- ratio)) tea time (h) phenylpropionate pionate 5 state yield (%) (OC) 23 Dioxane: water CH 2 Cl 2 110 216 54.3 ( 9: 1) 24 Dioxane: water CaCO 2 HO 64 56.6 10 (6: 4) 25 DMF: water (9: 1) CH 3 COOK 150 14 40.3 26 DMF: water (6: 4) CH 3 COOK 150 14 55, 6 27 DMF: water (6: 4) CaCC> 3 100 94 54.6 28 DMF: water (6: 4) CaCC> 3 100 72 54.4 15 29 DMSO: water (6: 4) CaCC> 3 100 94 54.3 30 DMSO: water (4: 6) CaCO 3 100 72 58.5 31 Anhydrous metal - 150x 7 34.2 methanol 32 Methanol: water CH 3 COOK 110 72 60.8 20 (7: 3) 33 Methanol: water CaCO 3 110 64 63.0 (6: 4) 34 Methanol: water CaCO 3 110 72 33.3 (4: 6) 25 35 Acetic acid CH 3 COOK 130 14 39.0 xHeated in a closed 30 ml tube Example 36 30 0.410 g 0 (- ( p-Toluenesulfonyloxy) -p-isobutylpropiophenone dimethyl acetal and 0.100 g of calcium carbonate were heated at reflux in a mixture of water and methanol (3: 7 by weight) for 22 hours, water (15 ml) was added and the mixture was extracted three times with 10 ml of diethyl ether. pest to 10 ml of water, dried over anhydrous magnesium sulfate and concentrated in vacuo, the oily residue was purified by column chromatography (silica gel, methylene chloride) to give 0.180 g of methyl O- (4-isobutylphenyl) -il as a colorless propionate: 23 7 5 3 3 6 propionate . Yield 81%. The values of the IR and NMR spectra of this product were exactly similar to those of the reference substance.

Example 37 0.910 g of Of- (p-toluenesulfonyloxy) -p-isobutylpropiophenone dimethyl acetal and 1.25 g of potassium carbonate were heated at reflux for 20 hours in a mixture of 25 ml of water and methanol (3: 7 by weight). Water (30 ml) was added and the mixture was washed with 10 ml of methylene chloride for 4-10 hours. The pH of the aqueous phase was adjusted to 2 with dilute hydrochloric acid and extracted with 20 ml of methylene chloride Four times. The extracts were washed with 30 ml of water, dried over anhydrous magnesium sulfate to give 0.335 g of O (- (4-isobutylphenyl) propionic acid as colorless crystals, m.p. 71-75 ° C. Yield 73%. IR and NMR spectrum of this product. values were exactly similar to the reference substance.

Example 38 0.991 g of O (- (methanesulfonyloxy) -p-isobutylpropiophenone dimethyl acetal and 0.300 g of calcium carbonate 20 were heated at reflux for 72 hours in a mixture of 10 ml of water and methanol (3: 7 by weight). hydrolysis as in Example 22 afforded 0.519 g of N- (4-isobutylphenyl) propionic acid as colorless crystals with a melting point of 73-75 ° C. Yield 84% The IR and NMR spectral values of this product were exactly the same as reference substance.

Example 39 2.12 g of Of- (p-toluenesulfonyloxy) -p-methoxypropionophenone dimethyl acetal and 0.560 g of calcium carbonate 30 were heated at reflux for 13 hours in a mixture of 20 ml of water and methanol (3: 7 by weight). Conventional recovery followed by alkaline hydrolysis of the crude product as in Example 22 afforded 0.714 g of Of- (4-methoxyphenyl) -propionic acid as pale yellow crystals with a melting point of 47-50 ° C. Yield 57%.

24 7 5 3 3 6

Example 40 0.735 g of QC- (methanesulfonyloxy) -p- (tert-butyl) -isovaleranephenone dimethyl acetal and 0.200 g of calcium carbonate were heated at reflux for 72 hours in a mixture of 10 ml of water and methanol (3: 7 by weight). Conventional recovery as in Example 36 and purification by column chromatography (silica gel, methylene chloride) afforded methyl OC - / - (tert-butyl) phenyl / isovalerate as a colorless oil.

IR (neat: 2965, 1745, 1165, 1025 cm NMR (CDCl 3): δ 0.71 (3H, d, J = 7 Hz), 1.02 (3H, d, J = 7 Hz), 1.32 (9H, s), 2.1-2.6 (1H, m), 3.10 (1H, d, J = 11Hz), 3.60 (3H, s), 7.1-7.4 ( 4H, m).

Elemental analysis for c 18 H 24 ° 2: 15 Calculated: C 77.37 H 9.74%

Found: C 77.26 H 9.62%

Example 41 0.668 g of 06- (p-toluenesulfonyloxy) acetophenone-ethylene acetal was dissolved in 8 ml of 1,3-dimethyl-2-imidat-20 solidin (DMI) and 200 mg of calcium carbonate and 0.2 ml of water were added to the solution. The mixture was heated to 180 ° C with stirring for 22 hours. After cooling, 30 ml of water were added and the mixture was extracted with 20 ml of diethyl ether three times. The extracts were washed twice with 10 ml of water and dried over anhydrous magnesium sulfate. The aqueous phases were combined and 4 ml of concentrated hydrochloric acid were added. The mixture was extracted with 20 ml of diethyl ether three times. The extracts were washed twice with 10 ml of water and dried over anhydrous magnesium sulfate. The extracts from the acidic and neutral conditions were concentrated under reduced pressure, the residue was combined and 400 ml of potassium hydroxide was added. The mixture was heated at reflux for 16 hours in a mixture of 6 ml of methanol and 2 ml of water. After cooling, 30 ml of water were added and the mixture was washed with 20 ml of diethyl ether three times. The aqueous phase was acidified to a pH of about 2 by adding about 7 ml of 3.5% hydrochloric acid and extracted with 20 ml of diethyl ether three times.

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25 7 5 3 3 6 times. The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 92 mg of a residue. This residue was found to be a mixture of benzoic acid and phenylacetic acid on the basis of its methyl esters obtained by diazomethane-5 treatment and analyzed by NMR and gas chromatography. The NMR spectrum showed that the mixture contained 65 mg (yield 27%) of benzoic acid and 27 mg (yield 10%) of phenylacetic acid.

Example 42 0.798 g of <X- (p-bromobenzenesulfonyloxy) acetophenone ethylene acetal was dissolved in 8 ml of DMI and 200 mg of calcium carbonate and 0.5 ml of water were added to the solution. The mixture was heated at 180 ° C for 18 hours with stirring. The reaction mixture was treated in the same manner and the crude product was subjected to basic hydrolysis as in Example 41 to give 84 mg of a semi-solid. By NMR spectroscopy, the semi-solid was found to be a mixture of benzoic acid and phenylacetic acid (7.0: 4.5 molar ratio). Similarly, the mixture was found to contain 49 mg (yield 20%) of benzoic acid and 35 mg (yield 13%) of phenylacetic acid.

Example 43 0.560 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propanone dimethyl acetal and 0.200 g of calcium carbonate were heated at reflux for 42 hours in a mixture of water and methanol (3: 7 by weight). Water (30 ml) was added and the mixture was extracted three times with 30 ml of diethyl ether. The extracts were washed twice with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 316 mg of methyl O- (- (2-thienyl) propionate as a colorless oil. The IR and NMR spectral values of this product were exactly the same as those of the reference substance. Yield 93% (crude).

The crude oil was distilled at 130 ° C (bath temperature) at 17 torr to give 279 mg of pure product. Yield 82% (after purification).

The aqueous phases of the extract were combined and 6 ml of concentrated hydrochloric acid were added. The mixture was extracted with 15 ml of diethyl 26,75336 ether three times. The extracts were washed twice with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 20 mg of Of- (2-thienyl) propionic acid as a colorless oil. Yield 6%. The IR and NMR spectral values of this product were exactly the same as those of the reference substance.

Example 44 0.565 g of 1- (2-thienyl) -2- (methanesulfonyloxy) -1-propanodimethylacetal and 0.202 g of calcium carbonate 10 were heated at reflux for 21 hours in a mixture of 6 ml of water and methanol (3: 7 by weight). 0.402 g of sodium hydroxide was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours and then heated under reflux for two hours. Water (30 ml) was added and the mixture was washed with 20 ml of diethyl ether. Concentrated hydrochloric acid (4 ml) was added to the aqueous phase, and the mixture was extracted with 20 ml of diethyl ether three times. The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.299 g of Of- (2-thienyl) -20-propionic acid as a colorless oil. Yield 95%.

Example 45

Sodium hydroxide (0.402 g) was dissolved in a mixture of 6 ml of water and raethanol (3: 7 by weight), and 0.574 g of 1- (2-thienyl) -2-methanesulfonyloxy) -25 1-propanone dimethyl acetal was added to the mixture. The mixture was heated at reflux for 21 hours. Water (40 ml) was added and the mixture was washed with 20 ml of diethyl ether. Concentrated hydrochloric acid (3 ml) was added to the aqueous phase, and the mixture was extracted with 20 ml of diethyl ether three times. The extracts were washed with 5 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.291 g of Ot- (2-thienyl) propionic acid as a colorless oil. Yield 91%.

Example 46 0.674 g of 1- (2-thienyl) -2- (p-toluenesulfonyloxy) -35 1-propanodimethylacetal and 0.200 g of calcium carbonate were heated at reflux for 12 hours in a mixture of 10 ml of water and methanol (3: 7 by weight). conventional

II

Recovery according to Example 36 afforded an oily crude product which was distilled at 110-120 ° C (bath temperature) and 17 torr to give 0.253 g of methyl α- (2-thienyl) propionate as a colorless oil. . Yield 79%.

Example 47 0.684 g of 1- (2-thienyl) -2- (benzenesulfonyloxy) -1-propanone dimethyl acetal and 0.200 g of calcium carbonate were heated at reflux for 8 hours in a mixture of 10 ml of water and methanol (3: 7 by weight). Conventional recovery as in Example 36 afforded an oily crude product which was distilled at 110 ° C (bath temperature) and 15 torr to give 0.277 g of methyl (X- (2-thienyl) propionate as a colorless oil. Yield 81%.

Example 48 0.299 g of Of- (methanesulfonyloxy) -p-acetylaminopropiophenone dimethyl acetal and 0.090 g of calcium carbonate were heated at reflux for 21 hours in a mixture of 3 ml of water and methanol (3: 7 by weight). Water (30 ml) was added and the mixture was extracted with 20 ml of methylene chloride three times. The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue. The residue was purified by column chromatography (silica gel, methylene chloride-diethyl ether) to give 0.186 g of methyl Of- (4-acetylaminophenyl) propionate as a colorless crystal.

Yield 93%, m.p. 107-109 ° C (from ethanol-hexane).

IR (KBr): 1740, 1665, 1610, 1555, 1515, 1415, 1330, 1160, 860, 840 cm -1.

NMR (CDCl 3): δ 1.46 (3H, d, J = 7 Hz), 2.11 (3H, s), δ 3.64 (3H, s), 3.67 (1H, q, J = 7 Hz), 7.17 (2H, d, J = 8 Hz), 7.53 (2H, d, J = 8 Hz), 8.17 (1H, broad s).

Elemental analysis for ci2H15NO3:

Calculated: C 65.14 H 6.83 N 6.33%

Found: C 64.94 H 7.00 N 6.27% 35 Example 49 0.329 g of OC- (benzenesulfonyloxy) -p-isobutyl-propiophenone dimethyl acetal and 0.10 g of calcium carbonate 75336 23 were heated under reflux for 10 hours in 10 ml of water. and a mixture of methanol (3: 7 by weight). Recovery in the same manner as in Example 48 and purification by column chromatography (silica gel, methylene chloride) afforded 0.181 g of 5-methyl-OC- (4-isobutylphenyl) propionate as a colorless oil. Yield 82%.

Example 50 0.392 g of Of- (benzenesulfonyloxy) -p-isobutylpropiophenone dimethyl acetal was heated in a mixture of 4 ml of water and pyridine (1: 3 by weight) in an oil bath at 100 ° C for 19 hours. Recovery similar to Example 48 and purification by column chromatography (silica gel, methylene chloride) afforded 0.164 g of methyl Of- (4-isobutylphenyl) propionate as a colorless oil. Yield 74%.

Example 51 0.392 g of (benzenesulfonyloxy) -p-isobutyl-propiophenone dimethyl acetal was mixed with a mixture of 10 ml of water and methanol (3: 7 by weight) and 2 ml of 10% aqueous potassium hydroxide, and the mixture was heated. refluxing for nine hours. Water (30 ml) was added and the mixture was washed with 15 ml of methylene chloride four times. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.138 g of Of- (4-isobutylphenyl) propionic acid as colorless crystals with a melting point of 73-75 ° C. Yield 67%.

Example 52 0.150 g of Of- (p-toluenesulfonyloxy) propiophenone diethyl acetal and 0.05 g of calcium carbonate were heated at reflux for 72 hours in a mixture of 10 ml of water and methanol (3: 7 by weight). Water (20 ml) was added and the mixture was extracted with 5 ml of diethyl ether four times and dried over anhydrous magnesium sulfate. The product was quantitatively analyzed by gas chromatography (using an internal standard) and found to contain 23 mg of ethyl O-phenyl-35 lipropionate in 32% yield.

Il 29 7 5 3 3 6

Example 53 0.978 g of (X- (methanesulfonyloxy) -p-fluoropropionophenone dimethyl acetal and 0.33 g of calcium carbonate were heated at reflux for 24 hours in a mixture of 15 ml of water and methane-5 (3: 7 by weight). By the same recovery and purification procedure , as in Example 49, 0.454 g of methyl Of- (4-fluorophenyl) propionate was obtained as a colorless oil.

Yield 76%.

10 IR (neat). 1744, 1607, 1513, 1460, 1439, 1340, 1230, 1210, 1170, 1160, 840, 796 cm -1.

NMR (CDCl 3): δ 1/46 (3H, d, J = 7 Hz), 3.60 (3H, s), 3.67 (1H, q, J = 7 Hz), 6.8 - 7.4 (4H, m).

Example 54 0.490 g of 1- (6-methoxy-2-naphthyl) -2- (methanesulfonyloxy) -1-propanodimethylacetal and 0.140 g of calcium carbonate were heated at reflux for 5 hours in 10 ml of water and dimethylformamide (1: 4 by weight). ) in the mixture. Water (20 ml) was added and the mixture was extracted with 7 ml of methylene chloride four times. The extracts were washed with 10 ml of water Four times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methylene chloride) to give 0.323 g of methyl (X- (6-methoxy-2-naphthyl) propionate as colorless crystals, m.p. 65-68 ° C. Yield 94%. and NMR spectral values were exactly the same as for the reference substance.

Example 55 0.354 g of 1- (6-methoxy-2-naphthyl) -2-methanesulfonyl-30-hydroxy-1-propanone dimethyl acetal and 0.10 g of calcium carbonate were heated at reflux for 28 hours in a mixture of 8 ml of water and methanol (3: 7 by weight). ). Water (20 ml) was added and the mixture was extracted three times with 10 ml of methylene chloride. The extracts were washed with 20 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.178 g of methyl O - (- (6-methoxy-2-naphthyl) propionate as colorless crystals. Yield 73%.

30 7 5 3 3 6

Example 56

Another of the possible stereoisomers of 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propanone dimethyl acetal was obtained, m.p. 102-105 ° C; Δ + 32.5 ° (c = 1, in chloroform) ./. 170 mg of this stereoisomer and 40 mg of calcium carbonate were heated to 110 ° C in a bath for 14 hours in a mixture of 5 ml of water and dimethylformamide (1: 4 by weight). Water (20 ml) was added and the mixture was extracted with 10 ml of diethyl ether four times. The extracts were washed with 10 ml of water four times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, methylene chloride) to give 68 mg of methyl (-) - O (- (6-methoxy-2-naphthyl) propionate as colorless crystals.

Yield 80.2%, m.p. 94.5-95 ° C.

Δ ^ -78.2 ° (c = 1, in chloroform).

IR (KBr): 2970, 1739, 1602, 1450, 1334, 1270, 1231, 1205, 1172, 1158, 1028, 893, 856, 823 cm-1.

The NRM spectrum of the product was the same as that of methyl OC- (6-methoxy-2-naphthyl) propionate obtained in Example 54.

Example 57 0.31 ml (0.44 g) of iodotrimethylsilane and two drops of cyclohexene were stirred in 5 ml of anhydrous methylene chloride at room temperature under argon. A solution of 4 ml of anhydrous methylene chloride and 529 mg of 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanone dimethyl acetal was added dropwise to the mixture. The mixture was stirred at room temperature for three hours. Then 5 ml of saturated aqueous sodium hydrogencarbonate solution was added. The organic phase was washed with 5 ml of 10% aqueous sodium thiosulfate solution, 5 ml of water, 5 ml of 10% aqueous sodium hydrogencarbonate solution and 5 ml of water, respectively, and dried over anhydrous magnesium sulfate. The product was quantitatively analyzed by gas chromatography (using an internal standard) and found to contain 226.4 mg of methyl Of phenylpropionate. Yield 91.9%.

Il 3, 75336

Examples 58-62 176 mg of 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanodimethylacetal and each of the oxygen affinity compounds shown in Table 2, given in Table 5, were stirred in 4 ml of anhydrous methylene chloride at the temperatures shown in Table 2. Water (5 ml) was added and the mixture was extracted with 5 ml of methylene chloride Four times. The extracts were washed with 10 ml of water and dried over anhydrous magnesium sulfate.

The product was analyzed for methyl Of phenylpropionate by gas chromatography in the same manner as in Example 57. The results are shown in Table 2.

Table 2

Eg Oxygen affinity- Reaction conditions Methyl-Of-phenylity- T ..__...... ... lipropionate Temperature Time r va compound (oc) (h) yield 58 AlCl-j (O / 6) 0 1 52.5 59 A1C13 (0.7) Reflux- 1 63.6 temperature 20 60 AlClj (1.0) Reflux- 0.7 69.3 temperature 61 a1C13 (1.4) 0 1 68.0 62 TiCl 4 (3.0) Reflux Temperature 25.8.8 Example 63 3.849 g of 1- (4-chlorophenyl) -2- (p-toluenesulfonyloxy) -1-propanodimethylacetal was stirred in 10 ml of anhydrous methylene chloride at room temperature under an argon atmosphere. . A solution obtained by dissolving 1.71 ml (2.40 g) of ioditrimethylsilane and two drops of cyclohexene in 2 ml of anhydrous methylene chloride was added dropwise to the mixture at room temperature, and the mixture was stirred for 30 minutes. The same recovery as in Example 57 gave an oily crude product which was found to contain 1.61 g of methyl C (- (p-chlorophenyl) propionate by NMR spectrum. Yield 81.0%.

32 7 5 3 3 6

Example 64 0.20 ml (0.28 g) of iodotrimethylsilane and one drop of cyclohexene were stirred in 8 ml of anhydrous methylene chloride at room temperature under argon. A mixture of 6 ml of anhydrous methylene chloride and 490 mg (1.00 mmol) of 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propanodimethylacetal was then added dropwise. (O = + 32.5 ° (c = 1.00, in chloroform), and the mixture was stirred at room temperature for 1 to 10 hours. 10 ml of saturated aqueous sodium hydrogencarbonate solution were added. Same recovery as in Example 57, followed by purification by column chromatography. (silica gel, methylene chloride) gave 230 mg of methyl (R) - (-) - (Xr (6-methoxy-2-naphthyl) propionate as colorless crystals with a melting point of 85-92 ° C. Yield 94.2% This product was found to be optically pure by NMR spectroscopy using optically active transition reagent Eu (TFC) 3.

Example 65

By the same procedure as in Example 17, 1- (4-methoxyphenyl) -2-hydroxy-1-propanodimethylacetal was prepared as a pale yellow oil from 1- (4-methoxyphenyl) -2-bromo-1-propanone. The crude product was used crude in the reaction of Example 66.

Example 66 In the same manner as in Example 7, 1- (4-methoxyphenyl) -2-methanesulfonyloxy-1-propanonimethylacetal was prepared as a pale yellow oil from 1- (4-methoxyphenyl) -2-hydroxy-1-propanodimethylacetal obtained in Example 65. Yield 80.1% calculated from 1- (4-methoxy-phenyl) -2-bromo-1-propanone.

IR (neat): 2935, 1615, 1517, 1358, 1257, 1176, 1100, 1065, 145, 915 cm-1.

NMR (CDCl 3): δ 1.18 (3H, d, J = 6 Hz), 3.09 (3H, s), 3.21 (3H, s), 3.28 (3H, s), 3.80 (3H, s), 4.97 (1H, 35q, J = 6 Hz), 6.87 (2H, d, J = 9 Hz), 7.37 (2H, d, J = 9 Hz).

Il 33 7 5 3 3 6

Example 67 1/007 g (3.308 mmol) of 1- (4-methoxyphenyl) -2-methanesulfonyloxy-1-propanone dimethyl acetal and 330 mg (3.30 mmol) of calcium carbonate were refluxed with stirring for 5 hours with 10 ml of water and methanol ( 3: 7 by weight) in the mixture. The same recovery and purification as in Example 49 gave 597 mg of methyl O- (4-methoxyphenyl) propionate as a colorless oil.

Yield 92.9%.

NMR (CDCl 3): δ 1.47 (3H, d, J = 7 Hz), 3.61 (3H, s), 3.67 (1H, q, J = 7 Hz), 3.73 (3H, s), 6.83 (2H, d, J = 9 Hz), 7.19 (2H, d, J = 9 Hz).

Example 68

In the same manner as in Example 20, 1- (2-thienyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethyl acetal was prepared as a colorless oil in 64% yield from 1- (2-thienyl) -2-hydroxy-1-propanone dimethyl acetal.

IR (neat): 1360, 1190, 1180, 1060, 985, 925, 905, 820, 790, 710, 665, 565 cm -1.

NMR (CDCl 3): δ 1.19 (3H, d, J = 7 Hz), 2.40 (3H, s), 3.08 (3H, s), 3.14 (3H, s), 4, 98 (1H, q, J = 7Hz), 6.94 (2H, d, J = 3Hz), 7.2-7.4 (3H, m), 7.80 (2H, d, J = 8). Hz).

Example 69 In the same manner as in Example 20, 1- (2-thienyl) -2- (benzenesulfonyloxy) -1-propanone dimethyl acetal was prepared as a colorless oil in 83% yield from 1- (2-thienyl) -2-hydroxy-1-propanodimethyl acetal. and benzenesulfonyl chloride.

IR (neat): 1360, 1190, 1060, 980, 925, 900, 590, 555 cm-1.

NMR (CDCl 3): δ 1.20 (3H, d, J = 7 Hz), 3.08 (3H, s), 3.14 (3H, s), 5.01 (1H, q, J = 7 Hz) ), 6.8-7.1 (2H, m), 7.2-7.4 (1H, m), 7.4-7.7 (3H, m), 7.9-8.1 (2H , m).

35 Example 70

Sodium metal (1.30 g, 56.5 mmol) was dissolved in 30 mL of anhydrous ethanol, and the mixture was stirred at 34,75336 room temperature. A solution of 20 ml of anhydrous ethanol and 5.33 g (0.035 mol) of α-bromopropiophenone was added dropwise to the solution over 15 minutes, and the mixture was stirred for another 40 minutes at room temperature. Water (100 ml) was added and the mixture was extracted with 60 ml of diethyl ether twice. The extracts were washed with water, dried over anhydrous potassium carbonate and concentrated under reduced pressure. The residue was dissolved in 30 ml of anhydrous ethanol in which a catalytic amount of sodium metal had been dissolved, and the mixture was stirred for two days at room temperature. Conventional recovery as in Example 3 gave 4.497 g of 1-phenyl-2-hydroxy-1-propanenediethyl acetal as a colorless oil.

Yield 80.2%.

15 IR (neat). 2960, 1452, 1120, 1092, 1040, 772, 709 cm-1.

NMR (CDCl 3): δ 0.94 (3H, d, J = 6 Hz), 1.05-1.40 (6H, m), 2.61 (1H, broad s), 3.22-3.83 (4H, m), 4.05 (1H, q, J = 6Hz), 7.1-7.7 (5H, m).

20 Example 71

Acetanilide (3.33 g) and 4.0 ml (5.2 g) of Of-chloropropionyl chloride were stirred at room temperature in 20 ml of carbon disulphide. 7.0 g of powdered aluminum chloride were then added portionwise over two minutes. The mixture was stirred at room temperature for 25 minutes and heated at reflux with stirring for 50 minutes. After cooling, two phases separated in the reaction mixture. The upper phase was removed by decantation and the lower phase, which was black and sharp, was poured into ice water. The precipitated crystals were collected by filtration. Crystallization from ethanol gave 1.860 g of 1- (4-acetylaminophenyl) -2-chloro-1-propanone as colorless crystals. The upper phase of the reaction mixture, the filtrate obtained by filtration of the crystals and the mother liquor of crystallization were combined and extracted with 50 ml of 35 methylene chloride three times. The extracts were washed with 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Recrystallization of the residue

II

35 75 3 3 6 of ethanol gave 1.434 g of 1- (4-acetylaminophenyl) -2-chloro-1-propanone. The mother liquor was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, methylene chloride and ether). Recrystallization from methanol 5 afforded an additional 0.868 g of the above product. The total amount of product was 4.162 g as a colorless paste and the total yield was 75%, m.p. 123-125 ° C (ethanol.

IR (KBr): 1690, 1675, 1595, 1540, 1415, 1320, 1360, 1180, 965, 860, 665 cm -1.

NMR (CDCl 3): δ 1.70 (3H, d, J = 7 Hz), 2.18 (3H, s), 5.18 (1H, q, J = 7 Hz), (2H, d, J = 9 Hz), 7.95 (2H, d, J = 9 Hz), 7.8-8.1 (1H, broad s).

Elemental analysis for C ^ H ^ CINC ^:

Calculated: C 58.54 H 5.36 Cl 15.71 N 6.21% 15 Found: C 58.59 H 5.40 Cl 15.63 N 6.23%

Example 72

In a similar manner to Example 17, 1- (4-acetylaminophenyl) -2-hydroxy-1-propanodimethylacetal was prepared as a glass from 1- (4-acetylamino-20-phenyl) -2-chloropropanone. The crude product was used crude in the reaction of Example 73.

NMR (CDCl 3): δ 0.95 (3H, d, J = 7 Hz), 2.14 (3H, s), 2.94 (1H, broad s), 3.21 (3H, s), 3, 33 (3H, s), 4.10 (1H, q, J = 7Hz), 7.37 (2H, d, J = 8Hz), 7.51 (2H, d, J = 25Hz), 8.93 (1H, broad s).

Example 73

All of the 1- (4-acetylaminophenyl) -2-hydroxy-1-propanone dimethyl acetal obtained in Example 72 was dissolved in 5 ml of pyridine, and 0.60 ml (0.89 g) of methanesulfonyl chloride was added to the solution. The mixture was stirred at room temperature for five hours. The reaction mixture was cooled with ice, and 30 ml of water was added thereto. The temperature was raised to room temperature and the mixture was stirred for 10 minutes and extracted with 20 ml of ethyl acetate four times. The extract 35 was dried by successively adding anhydrous sodium sulfate and anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (florisil, methyl enichloride and diethyl ether) to give 1.537 g of 1- (4-acetylaminophenone) -2-methanesulfonyloxy-1-propanone dimethyl acetal as a colorless glass. Yield 93% / calculated 1- (4-acetylaminophen-5-yl) -2-chloro-1-propanone.

IR (KBr): 1675, 1610, 1540, 1350, 1175, 915, 525 cm-1. NMR (CDCl 3): δ 1.14 (3H, d, J = 7 Hz), 2.52 (3H, s), 3.08 (3H, s), 3.18 (3H, s), 3.24 (3H, s), 4.94 (1H, q, J = 7Hz), 7.36 (2H, d, J = 9Hz), 7.54 (2H, d, J = 9Hz), 10 , 52 (1H, broad s).

Example 74

In the same manner as in Example 17, 1- (4-fluorophenyl) -2-hydroxy-1-propanone dimethyl acetal was prepared as a pale yellow oil from 1- (4-fluorophenyl) -2-bromo-1-propanone. This product was used crude in the reactions of Examples 70 and 76.

IR (neat): 2975, 2937, 1610, 1512, 1230, 1159, 1105, 1053, 982, 839 cm -1.

NMR (CDCl 3): δ 0.93 (3H, d, J = 6 Hz), 2.53 (1H, 20 broad s), 3.23 (3H, s), 3.33 (3H, s), 4 .08 (1H, broad q, J = 6 Hz), 6.83 - 7.18 (2H, m), 7.32 - 7.60 (2H, m).

Example 75

By the same procedure as in Example 7, 1- (4-fluorophenyl) -2-methanesulfonyloxy-1-propano-25-dimethylacetal was prepared as a colorless oil from 1- (4-chlorophenyl) -2-hydroxy-1-propanone dimethylacetal obtained from Example 74. Yield 82, 3% / calculated 1- (4-fluorophenyl) -2-bromo-1-propanone% 7 · IR (neat): 2940, 1610, 1512, 1359, 1228, 1180, 30 1160, 1098, 1067, 1045, 972, 918 cm "1.

NMR (CDCl 3): δ 1.15 (3H, d, J = 6 Hz), 3.06 (3H, s), 3.21 (3H, s), 3.24 (3H, s), 4.96 (1H, q, J = 6 Hz), 6.88 - 7.16 (2H, m), 7.32 - 7.58 (2H, m).

Example 76 In the same manner as in Example 20, 1- (4-fluorophenyl) -2- (p-toluenesulfonyloxy) -1-propanodimethylacetal was prepared as colorless crystals having

II

37,75336 had a melting point of 96-99 ° C from 1- (4-fluorophenyl) -2-hydroxy-1-propanodimethylacetal obtained in Example 74. Yield 76.2% / calculated 1- (4-fluorophenyl) -2-bromo-1 -Pro-panonista /.

5 Sp. 101 ° C (from methanol).

IR (KBr): 2948, 1605, 1510, 1360, 1346, 1192, 1181, 1090, 1053, 932, 918, 820, 786, 670, 561 cm-1.

NMR (CDCl 3): δ 1/05 (3H, d, J = 6 Hz), 2.40 (3H, s), 3.08 (3H, s), 3.10 (3H, s), 4.93 (1H, q, J = 6 Hz), δ 6.82 - 7.08 (2H, m), 7.16 - 7.46 (4H, m), 7.73 (2H, d, J = 8 Hz) ).

Elemental analysis for cigH21F03S:

Calculated: C 58.68 H 5.75%

Found: C 58.98 H 5.96% Example 77 8.57 g of 1- (6-methoxy-2-naphthyl) -1-propanone (U.S. Patent No. 2,683,738) was dissolved in 60 ml of anhydrous di- the oxane and solution were stirred at room temperature. To the solution was added 13.57 g of pyridyl hydrobromoperbromide, after which the mixture was stirred for another hour. To the mixture was added 200 ml of 3% aqueous sodium bisulfite solution, and after stirring for 3 hours at room temperature, the precipitated crystals were filtered off, washed with water and dried under reduced pressure over potassium hydroxide to give 11.66 g of 1- (6-methoxy-2-naphthyl) - 2-Bromo-1-propanone with a melting point of 73-75 ° C as pale yellow crystals.

Yield 99%, m.p. 68-69 ° C (from benzene).

NMR (CDCl 3): δ 1.90 (3H, d, J = 7 Hz), 3.85 (3H, s), δ 5.36 (1H, q, J = 7 Hz), 6.9-7, Δ (2H, m), 7.5-8.1 (3H, m), 8.38 (1H, broad s).

Elemental analysis for C ^ H ^ gBrCl 2:

Calculated: C 57.35 H 4.47 Br 27.26%

Found: C 57.27 H 4.66 Br 27.23% 35 Example 78

By a similar procedure to Example 3, 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone-38 7 5 3 3 6 dimethyl acetal was prepared as a colorless oil 1- (6-methoxy-2-naphthyl) -2 bromo-l-propanone. Yield 100%. After purification by column chromatography (florisiil, methylene chloride), the product crystallized on standing at room temperature.

Colorless crystals. Sp. 56-59 ° C.

IR (KBr): 3500, 1637, 1610, 1488, 1276, 1215, 1175, 1118, 1106, 1040, 859 cm -1.

NMR (CDCl 3): δ 0.97 (3H, d, J = 7 Hz), 2.48 (1H, 10 broad s), 3.20 (3H, s), 3.36 (3H, s), 3.82 (3H, s), 4.14 (1H, q, J = 7Hz), 7.00-7.24 (2H, m), 7.40-7.98 (4H, m).

Elemental analysis for c 18 H 20 O 4:

Calculated: C 69.54 H 7.30%

Found: C 69.25 H 7.28% Example 79

In a similar manner to Example 7, 1- (6-methoxy-2-naphthyl) -2-methanesulfonyloxy-1-propanone dimethyl acetal was prepared as a colorless oil from 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone dimethyl acetate. list. Yield 84%.

IR (neat): 1640, 1615, 1492, 1360, 1280, 1182, 901, 820 cm -1.

NMR (CDCl 3): δ 1/19 (3H, d, J = 7 Hz), 3.09 (3H, s), 3.22 (3H, s), 3.31 (3H, s), 3.87 (3H, s), 5.05 (1H, 25q, J = 7Hz), 7.04-7.24 (2H, m), 7.42-7.94 (4H, m). Elemental analysis for C 17 H 27 O 2 S:

Calculated: C 57.61 H 6.26 S 9.05%

Found: C 57.21 H 6.02 S 8.85%

Example 80 350 mg of sodium metal was dissolved in 40 ml of anhydrous methanol, and the solution was stirred at room temperature. To the solution was added 2.93 g of 1- (6-methoxy-2-naphthyl) -2-bromo-1-propanone, and the mixture was stirred for 24 hours. To the mixture was added 50 ml of water, which was then extracted with methylene chloride (15 ml x 4). The extract was dried over anhydrous magnesium sulfate and anhydrous potassium carbonate and concentrated under reduced pressure to give 2.845 g of 1- (6-methoxy-

II

39 7 5 3 3 6 2-Naphthyl) -2-hydroxy-1-propanone dimethyl acetal as a crude product. 1.11 g of the crude product was dissolved in 3 ml of anhydrous pyridine, and the solution was stirred at room temperature. To the solution was added 993 mg of d-10-camphorsulfonyl-5 chloride, and the mixture was stirred for 40 minutes. To the mixture was added 20 ml of water, which was then extracted with methylene chloride (10 ml x 3). The extract was dried by successively adding anhydrous magnesium sulfate and anhydrous potassium carbonate, and concentrated under reduced pressure. The oil obtained as residue 10 was purified by column chromatography (Fluorosil, methylene chloride) to give 1.467 g of 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propanedimethylacetal as a colorless glass. Yield 76.8% (calculated from 1- (6-methoxy-2-naphthyl) -2-bromo-15 ml-1-propanone). The product was found to be a 1: 1 mixture of both stereoisomers by HPLC liquid chromatography and NMR spectrum.

1.067 g of the product thus obtained was dissolved in 4 ml of methanol, and the solution was allowed to stand for two days at 2-4 ° C to form 355 mg of colorless crystals having a melting point of 90-95 ° C. The crystals were further recrystallized from methanol to give 220 mg of the second stereoisomer as a pure product.

Sp. 102-105 ° C.

25 + 32.5 ° (c = 1, in chloroform).

IR (KBr): 2950, 1753, 1634, 1611, 1487, 1354, 1273, 1219, 1180, 1166, 1068, 1042, 990, 899, 862, 840 cm-1.

NMR (CDCl 3): δ 0.87 (3H, s), 1.12 (3H, s), 1.23 (3H, d, J = 6 Hz), 1.3-2.7 (7H, m) , 3.04 (1H, d, J = 30 Hz), 3.24 (3H, s), 3.35 (3H, s), 3.86 (3H, s), 3.86 (1H, d), , J = 15 Hz), 5.15 (1H, q, J = 6 Hz), 7.04 - 7.26 (2H, m), 7.46 - 7.98 (4H, m).

Elemental analysis for C26H33 ° 7S:

Calculated: C 63.78 H 6.79 S 6.55% 35 Found: C 63.66 H 7.06 S 6.57%

The second stereoisomer was separated from the mixture by HPLC liquid chromatography as a colorless oil / column: 40 75 3 36

Microporasil, manufactured by Waters Co .; column size: 7.8 mm x 30 cm; eluent: hexane + ethyl acetate (9: 1) ./.

+ 4.2 ° (c = 0.143, in chloroform).

IR (KBr): 2950, 1750, 1631, 1608, 1485, 1352, 1271, δ 1216, 1172, 1062, 1040, 985, 914, 895, 855, 810 cm -1.

NMR (CDCl 3): δ 0.91 (3H, s), 1.14 (3H, s), 1.26 (3H, d, J = 6 Hz), 1.3 - 2.7 (7H, m) , 3.29 (1H, d, J = 15 Hz), 3.30 (3H, s), 3.42 (3H, s), 3.74 (1H, d, J = 15 Hz), 3.96 (3H, s), 5.20 (1H, q, J = 6Hz), 7.10-7.30 (2H, m), 7.50-8.02 (4H, m).

Example 81 1.922 g (5,000 mmol) of 1- (4-chlorophenyl) -2- (p-toluenesulfonyloxy) -1-propanodimethylacetal and 500 mg (5.00 mmol) of calcium carbonate were heated with stirring at 110 ° C (bath temperature ) for three days in a mixture of dimethylformamide and water (4 + 1 by weight). Conventional recovery as in Example 36 gave 337 mg of a colorless oil, which was found to contain 238 mg of methyl OC- (4-chlorophenyl) propionate by NMR spectroscopy.

Yield 12.0%.

Example 82 Using a procedure similar to Example 17, 1- (4-chlorophenyl) -2-hydroxy-1-propanone dimethyl acetal was prepared as a colorless oil from 1- (4-chlorophenyl) -25 2-bromo-1-propanone. This product was used without further purification in the reaction of Example 83.

IR (neat): 3450, 2975, 2930, 1600, 1492, 1398, 1108, 1095, 1052, 1016, 980, 829, 743 cm -1.

Example 83 In the same manner as in Example 20, 1- (4-chlorophenyl) -2- (p-toluenesulfonyloxy) -1-propanonimethylacetal was prepared as white crystals having a melting point of 76-77 ° C, 1- (4-chlorophenyl) - From 2-hydroxy-1-propanonimethylacetal obtained in Example 82.

Yield 86% (calculated on 1- (4-chlorophenyl) -2-bromo-1-propanone).

Sp. 78-79 ° C (from methanol).

IR 75336 41 IR (KBr): 2945, 1601, 1493, 1364, 1347, 1195, 1188, 1094, 1057, 1110, 936, 919, 822, 789, 669, 565 cm-1.

NMR (CDCl 3): δ 1.05 (3H, d, J = 6 Hz), 2.40 (3H, s), 3.08 (3H, s), 3.10 (3H, s), 4.93 (1H, q, J = 6 Hz), 7.25 δ (4H, s), 7.27 (2H, d, J = 8 Hz), 7.76 (2H, d, J = 8 Hz). Elemental analysis for ciqH21SO3Cl:

Calculated: C 56.17 H 5.50 Cl 9.21 S 8.33%

Found: C 56.22 H 5.48 Cl 9.13 S 8.32%

Example 84 In the same manner as in Example 71, 1- [4- (1-oxo-2-isoindolinyl) phenyl] -2-chloro-1-propanone was prepared as a colorless crystal in 89% yield from 2-phenyl-1-isoindolinone and Ct-chloropropionyl chloride.

Example 85 In the same manner as in Example 17, 1- [4- (1-oxo-2-isoindolinyl) phenyl] -2-hydroxy-1-propanone was obtained in 83% yield as colorless crystals with a melting point of 130-135 ° C.

IR (KBr): 3530, 1680, 1515, 1385, 1310, 1120, 1045, 20 740 cm -1.

NMR (CDCl 3): δ 0.96 (3H, d, J = 7 Hz), 2.36 (1H, broad s), 3.20 (3H, s), 3.33 (3H, s), 4, Δ (1H, broad q, J = 7 Hz), 4.80 (2H, s), 7.4-7.6 (5H, m), 7.8-8.0 (3H, m).

Elemental analysis for c19H21NO4:

Calculated: C 69.70 H 6.47 N 4.28%

Found: C 69.63 H 6.49 N 4.21%

Example 86

In the same manner as in Example 73, 1- [4- (1-oxo-2-isoindolinyl) phenyl] -2-methanesulfonyloxy-1-propanodimethylacetal 1- [4- (1-oxo-2-isoindolinyl) phenyl] From 2-hydroxy-1-propanodimethylacetal and methanesulfonyl chloride in 95% yield as colorless crystals.

IR (KBr): 1695, 1520, 1390, 1350, 1340, 1175, 975, 910, 740 cm-1.

75336 42 NMR (CDCl 3): δ 1.20 (3H, d, J = 7 Hz), 3.11 (3H, s), 3.24 (3H, s), 3.30 (3H, s), 4.81 (2H, s), 5.00 (1H, q, J = 7Hz), 7.4-7.6 (5H, m), 7.8-8.0 (3H, m).

Example 87 In the same manner as in Example 48, methyl O- [1- (1-oxo-2-isoindolinyl) phenyl] propionate 1- [4- (1-oxo-2-isopropylate) was prepared in 86% yield as a colorless cake. indolinyl) fenyyli7-2-methanesulfonyloxy-l-propanone dimethyl acetal.

10 Example 88

In the same manner as in Example 17, 1- (4-biphenyl) -2-hydroxy-1-propanone dimethyl acetal was prepared from 1- (4-biphenyl) -2-bromo-1-propanone in 95% yield as a colorless crystal with a melting point of 78 , Δ -15 80 ° C.

Sp. 78.5-80 ° C (from ether / n-hexane).

IR (KBr): 1118, 1102, 1045, 1007, 979, 838, 770, 735, 695 cm-1.

NMR (CDCl 3): 61.00 (3H, d, J = 7 Hz), 2.44 (1H, 20 d, J = 3.1 Hz), 3.23 (3H, s), 3.37 (3H , s), 4.12 (1H, q, d, J = 7 Hz, 3.1 Hz), 7.2-7.7 and 7.55 (m and s, 9H).

Elemental analysis for C 7 H 20 O 3:

Calculated: C 74.97 H 7.40%

Found: C 74.88 H 7.27% Example 89

In the same manner as in Example 7, 1- (4-biphenyl) -2-methanesulfonyloxy-1-propanone dimethyl acetal was prepared from 1- (4-biphenyl) -2-hydroxy-1-propanone dimethyl acetal as a colorless oil. This product was used crude for the Example 90 reaction.

IR (neat): 1490, 1357, 1335, 1177, 1123, 1100, 1065, 1045, 971, 916, 847, 811, 773, 753, 740, 702, 538, 527 cm-1.

NMR (CDCl 3): δ 1.21 (3H, d, J = 7 Hz), 3.03 (3H, s), δ 3.24 (3H, s), 3.31 (3H, s), δ, 01 (1H, q, J = 7 Hz), 7.1-7.7 (m) - 7.56 (s) total 9H.

Il 43 75 336

Example 90

In the same manner as in Example 21, methyl OC- (4-biphenyl) propionate was prepared from 1- (4-biphenyl) -2-methanesulfonyloxy-1-propanodimethylacetal obtained in Example 89. Yield 80% / calculated 1- (4 -biphenyl) -2-hydroxy-1-propanone dimethyl acetal7.

IR (neat): 1741, 1490, 1215, 1167, 765, 701 cm-1.

NMR (CDCl 3): δ 1/47 (3H, d, J = 7 Hz), 3.55 (3H, s), 3.68 (1H, q, J = 7 Hz), 7.1 - 7.56 (9 H, m).

10 Example 91

In the same manner as in Example 57, methyl (X- (4-biphenyl) propionate was prepared from 1- (4-biphenyl) -2-methanesulfonyloxy-1-propanone dimethyl acetal obtained in Example 89. Yield 68% / calculated 1- (4-15 biphenyl ) -2-hydroxy-l-propanonidimetyylliasetaalista7.

Example 92

In the same manner as in Example 17, 1,1-dimethoxy-2-hydroxy-1,2,3,4-tetrahydronaphthalene was prepared from 2-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene. This product was used crude in the reaction of Example 93.

IR (neat): 1138, 1080, 1058, 767 cm

Example 93

In the same manner as in Example 7, 1,1-dimethoxy-2-methanesulfonyloxy-1,2,3,4-tetrahydronaphthalene was prepared as colorless crystals, m.p. 113-114.5 ° C, from 1,1-dimethoxy obtained from Example 92. -2-hydroxy-1,2,3,4-tetrahydronaphthalene. Yield 46.5% (calculated from 2-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene).

30 Sp. 113-114.5 ° C (methylene chloride / diethyl ether / n-hexane).

IR (KBr): 1361, 1340, 1206, 1175, 1141, 1033, 1060, 1050, 981, 959, 949, 847, 781, 768, 625, 546, 530, 510 cm -1.

NMR (CDCl 3): δ 2.37 (2H, m), 2.9 (2H, m), 2.94 (3H, 35 s), 2.98 (3H, s), 3.43 (3H, s) ), 5.27 (1H, t, J = 3 Hz), 7.17 (3H, m), 7.63 (1H, m).

44 7 5 3 3 6

Elemental analysis for C ^ 3H ^ 8 ° 5S:

Calculated: C 54.53 H 6.34 S 11.20%

Found: C 54.73 H 6.36 S 11.10%

Example 94 In a similar manner to Example 54, methyl indane-1-carboxylate was prepared from 1,1-dimethoxy-2-methanesulfonyloxy-1,2,3,4-tetrahydronaphthalene.

Example 95

In a similar procedure to Example 58, methyl N-phenylpropionate was prepared in 51.4% yield from 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanodimethylacetal and tin chloride.

Example 96

In the same manner as in Example 77, 2-bromo-1- (4-difluoromethoxyphenyl) -1-propanone was prepared as a colorless oil from 1- (4-difluoromethoxyphenyl) -1-propanone.

NMR (CDCl 3): δ 1/92 (3H, d, J = 7 Hz), 5.23 (1H, q, J = 7 Hz), 6.58 (1H, t, J = 72 Hz), δ, 15 (2H, d, J = 9 Hz), 8.00 (2H, d, J = 9 Hz).

20 Example 97

In a similar manner to Example 17, 1- (4-difluoromethoxyphenyl) -2-hydroxy-1-propanone dimethyl acetal was prepared as a colorless oil from 2-bromo-1- (4-difluoromethoxyphenyl) propanone.

IR (neat): 3600-3200, 1515, 1385, 1230, 1130, 1050, 840 cm-1.

NMR (CDCl 3): δ 0.95 (3H, d, J = 7 Hz), 2.37 (1H, d, J = 3 Hz), 3.23 (3H, s), 3.33 (3H, s ), 4.10 (1H, dq, J = 3 ha at 7 Hz), 6.52 (1H, t, J = 74 Hz), 7.10 (2H, d, J = 9 Hz), 7.49 (2H, d, J = 9Hz).

Example 98

In the same manner as in Example 7, 1- (4-difluoromethoxyphenyl) -2-methanesulfonyloxy-1-propanone dimethyl acetal was prepared as a colorless oil from 1- (4-di-35-fluoromethoxyphenyl) -2-hydroxy-1-propanone dimethyl acetal obtained in Example 97. Yield 55% / calculated from 1- (4-difluoromethoxyphenyl) -1-propanone.

IR 75336 45 IR (neat): 1515, 1360, 1235, 1180, 1130, 1100, 1070, 1045, 975, 920, 540, 530 cm -1.

NMR (CDCl 3): δ 1.18 (3H, d, J = 7 Hz), 3.09 (3H, s), 3.15 (3H, s), 3.18 (3H, s), 4.98 (1H, q, J = 7 Hz), 6.53 δ (1H, t, J = 7 Hz), 7.10 (2H, d, J = 9 Hz), 7.45 (2H, d, J = 9 Hz).

Example 99

In the same manner as in Example 77, 2-bromo-1- (4-difluoromethoxyphenyl) -3-methyl-1-butanone was prepared as a colorless oil from 1- (4-difluoromethoxyphenyl) -3-methyl-1-butanone.

IR (neat): 1690, 1605, 1230, 1120, 1055 cm-1.

NMR (CDCl 3): δ 1.02 (3H, d, J = 7 Hz), 1.21 (3H, d, J = 7 Hz), 2.1-2.8 (1H, m), 4, 85 (1H, d, J = 9 Hz), 6.60 (1H, t, J = 7 Hz), 7.18 (2H, d, J = 9 Hz), 8.03 (2H, d, J = 9 Hz).

Example 100

In the same manner as in Example 17, 1- (4-difluoromethoxyphenyl) -2-hydroxy-3-methyl-1-buta-20-nonidimethylacetal was prepared as a colorless oil from 2-bromo-1- (4-difluoromethoxyphenyl) -3-methyl-1-butanone.

IR (neat): 3600-3300, 1515, 1390, 1230, 1130, 1050 cm -1.

NMR (CDCl 3): δ 0.69 (3H, d, J = 6 Hz), 0.88 (3H, 25 d, J = 6 Hz), 1.2-1.7 (1H, m), 2, 50 (1H, d, J = 3 Hz), 3.22 (3H, s), 3.24 (3H, s), 3.70 (1H, dq, J = 4 and 6 Hz), 6.50 ( 1H, t, J = 74 Hz), 7.07 (2H, d, J = 9 Hz), 7.52 (2H, d, J = 9 Hz).

Example 101 In the same manner as in Example 13, 1- (4-difluoromethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal was prepared as a colorless oil 1- (4-difluoromethoxyphenyl) -2-hydroxy-3-methyl-1-bu -tanonidimetyyliasetaalista. Yield 76% / calculated from 1- (4-35 difluoromethoxyphenyl) -3-methyl-1-butanone7.

This product crystallized spontaneously at low temperature.

4Q 7 5 3 3 6

Sp. 60-61 ° C.

IR (KBr): 1515, 1350, 1230, 1180, 1145, 1080, 1055, 1035, 975 cm-1.

NMR (CDCl 3): δ 0.67 (3H, d, J = 6 Hz), 0.91 (3H, d, δ J = 6 Hz), 1.4-1.9 (1H, m), δ , 17 (3H, s), 3.19 (3H, s), 3.22 (3H, s), 4.75 (1H, d, J = 4 Hz), 6.50 (1H, t, J = 74 Hz), 7.08 (2H, d, J = 9 Hz), 7.50 (2H, d, J = 9 Hz).

Example 102

In a similar manner to Example 53, N- (4-difluoromethoxyphenyl) propionate was prepared in 51% yield from 1- (4-difluoromethoxyphenyl) -2-methanesulfonyloxy-1-propanone dimethylacetate obtained in Example 98.

IR (neat): 1745, 1515, 1385, 1230, 1160, 1130, 15 1050 cm-1.

NMR (CDCl 3): δ 1.46 (3H, d, J = 7 Hz), 3.61 (3H, s), 3.67 (1H, q, J = 7 Hz), 6.43 (1H, t , J = 74 Hz), 7.02 (2H, J = 9 Hz), 7.26 (2H, J = 9 Hz).

Example 103 0.368 g of 1- (4-difluoromethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal and 0.100 g of calcium carbonate were heated at reflux in 3 ml of a mixture of water and methanol (3: 7 by weight) for 18 days. Conventional recovery followed by chromatographic separation afforded 0.132 g of methyl N- (4-difluoromethoxyphenyl) isovalerate as a colorless oil.

Yield 51%.

NMR (CDCl 3): δ $ 0.71 (3H, d, J = 7 Hz), 1.02 (3H, d, J = 7 Hz), 2.0 - 2.5 (1H, m), δ, 14 (1H, d, J = 11 Hz), 3.63 (3H, s), 6.47 (1H, t, J = 74 Hz), 7.02 (2H, d, J = 9 Hz), 7.31 (2H, d, J = 9Hz).

Example 104 In 3 ml of a mixed solvent of water and DMF (1: 4 by weight), 0.368 g of 1- (4-difluoromethoxy-35-phenyl) -2-methanesulfonyloxy-3-methyl-1-butanone and 0.100 g of calcium carbonate were heated at 110 °. In C for 12 days, followed by reflux for three days. conventional

II

After recovery and separation, 78 mg of methyl Of- (4-difluoromethoxyphenyl) isovalerate were obtained. Yield 30%.

Example 105 230 mg of sodium metal was dissolved in 3 ml of anhydrous methanol. To the solution were added a mixture of 2 ml of anhydrous methanol and 1.43 g of 2-bromo-1- (4-ethoxyphenyl) -3-methyl-1-butanone. The mixture was stirred at room temperature for 1.5 hours, then at 50 ° C for 45 minutes. Conventional recovery afforded 1.344 g of 1- (4-ethoxyphenyl) -10 2-hydroxy-3-methyl-1-butanone dimethyl acetal as a crude crude product as a colorless oily substance. The crude product was used for the reaction of Example 106.

IR (neat): 3600-3399, 1610, 1515, 1485, 1400, 1250, 1175, 1115, 1050, 990, 925, 840, 810 cm -1.

NMR (CDCl 3): δ 0.68 (3H, t, J = 6 Hz), 0.87 (3H, d, J = 6 Hz), 1.39 (3H, t, J = 7 Hz), 1 , 2 - 1.7 (1H, m), 2.50 (1H, d, J = 3 Hz), 3.22 (3H, s), 3.24 (3H, s), 3.68 (1H, dd, J = 3 and 5 Hz), 4.01 (2H, q, J = 7 Hz), 6.82 (2H, d, J = 9 Hz), 7.37 (2H, d, J = 9 Hz) ).

20 Example 106

In the same manner as in Example 13, 1- (4-ethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal was prepared as a colorless kit from 1- (4-ethoxyphenyl) -2-hydroxy-3-methyl-1-butanone dimethyl acetal obtained in Example 105. . Yield 62% / calculated from 2-bromo-1- (4-ethoxyphenyl) -3-methyl-1-butanone7.

Sp. 83-87 ° C.

IR (KBr): 1610, 1335, 1260, 1245, 1175, 955, 850, 840 cm -1.

NMR (CDCl 3): δ 0.71 (3H, d, J = 6 Hz), 0.94 (3H, d, J = 6 Hz), 1.40 (3H, t, J = 7 Hz), 1 Δ - 1.9 (1H, m), 3.18 (3H, s), 3.20 (3H, s), 3.24 (3H, s), 4.02 (2H, q, J = 7) Hz), 4.57 (1H, d, J = 3 Hz), 6.85 (2H, d, J = 9 Hz), 7.37 (2H, d, J = 9 Hz).

Example 107 724 mg of 1- (4-ethoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal and 200 mg of calcium 43,75336 carbonate were heated at reflux for 11 hours in 7 ml of water and methanol (3: 7 by weight). in the mixture. After the usual recovery and purification, 467 mg of methyl Otf- (4-ethoxyphenyl) isovalerate was obtained as a colorless oil.

Yield 99%, b.p. 160 ° C (bath temperature / 17 torr.

NMR (CDCl 3): δ 0.70 (3H, d, J = 6 Hz) f 1.01 (3H, d, J = 6 Hz), 1.38 (3H, t, J = 7 Hz), 2, 0 - 2.6 (1H, m), 3.07 (1H, d, J = 10 Hz), 3.30 (3H, s), 3.97 (2H, q, J = 7 Hz), .80 (2H, d, J = 9 Hz), 7.20 (2H, d, J = 9 Hz).

Elemental analysis for c 14 H 20 O 3:

Calculated: C 71.16 H 8.53%

Found: C 70.93 H 8.52%

Example 108 In the same manner as in Example 105, 2.58 g of 1- (4-methoxyphenyl) -2-hydroxy-3-methyl-1-butanone dimethyl acetal as a colorless oil was prepared as a crude oil from 2.71 g of 2-bromo-1- (4- methoxyphenyl) -3-methyl-1-butanone and the product was used crude in the reaction of Example 20 109.

IR (neat): 3600-3300, 1615, 1515, 1255, 1175, 1115, 1045, 840 cm-1.

NMR (CDCl 3): $ 0.70 (3H, d, J = 6 Hz), 0.87 (3H, d, J = 6 Hz), 1.2-1.7 (1H, m), 2.53 (1H, broad s), 3.33 (3H, s), 3.34 (3H, s), 3.68 (1H, d, J = 5 Hz), 3.78 (3H, s), 6 .83 (2H, d, J = 9 Hz), 7.40 (2H, d, J = 9 Hz).

Example 109 2.58 g of 1- (4-methoxyphenyl) -2-hydroxy-3-methyl-1-butanone dimethyl acetal 30 prepared in Example 108 were dissolved in 5 ml of anhydrous pyridine, and the mixture was stirred under ice-cooling. To the solution was added 2.00 g of methanesulfonic anhydride, and the mixture was stirred for four hours under ice-cooling, and then for two hours at room temperature. To the mixture was added 20 ml of water, and the mixture was stirred for one hour at room temperature, extracted with 20 ml of diethyl ether three times. The extracts were washed with 5 ml of water twice and dried over anhydrous magnet 49 7 5 3 3 6 zinc sulfate and concentrated under reduced pressure, the oily residue was purified by column chromatography (florisil, methylene chloride) to give 3.10 g of 1- (4-methoxyphenyl) -2-raethanesulfone -3-methyl-1-butanone dimethylacetate-5 as a colorless oil (the product crystallized on its own when standing at room temperature). Yield 93 L / calculated from 2-bromo-1- (4-methoxyphenyl) -3-methyl-1-butanone7.

Sp. 71.5-73 ° C.

IR (KBr): 1620, 1525, 1355, 1260, 1180, 1105, 1055, 10980, 970, 960, 945, 865, 850 cm-1.

NMR (CDCl 3): δ 0.68 (3H, d, J = 6 Hz), 0.89 (3H, d, J = 6 Hz), 1.5-1.9 (1H, m), 3.14 (3H, s), 3.16 (3H, s), 3.21 (3H, s), 3.76 (3H, s), 4.72 (1H, d, J = 4 Hz), 6.82 (2H, d, J = 9 Hz), 7.36 (2H, d, J = 9 Hz).

15 Example 110

In the same manner as in Example 107, methyl δ (“(4-methoxyphenyl) isovalerate as a colorless oil was prepared from 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone dimethyl acetal.

20 Yield 94%.

IR (neat): 1740, 1515, 1255, 1160, 1040, 830 cm-1.

NMR (CDCl 3): δ 0.70 (3H, d, J = 6 Hz), 1.00 (3H, d, J = 6 Hz), 2.0 - 2.6 (1H, m), 3.08 (1H, d, J = 10 Hz), 3.63 (3h, s), 3.78 (3H, s), 6.80 (2H, d, J = 9 Hz), 7.21 (2H, d, J = 9 Hz).

Example 111 To a suspension of 0.65 g of sodium hydride (55% in mineral oil) and 10 ml of anhydrous tetrahydrofuran was added 2.7 ml of ethylene glycol under ice-cooling. After the reaction mixture was stirred for 40 minutes at room temperature, 2.71 g of 2-bromo-1- (4-methoxyphenyl) -3-methyl-1-butanone was added thereto, and the mixture was stirred for 12 hours at 60 ° C. After addition of water (50 ml), the reaction mixture was extracted three times with 30 ml of methylene chloride. The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the oily residue was purified by column chromatography (florisil, 50 75 3 3 6 methylene chloride) to give 719 mg of 2-hydroxy-1- (4-methoxyphenyl). -3-methyl-1-butanone ethylene acetal as a colorless oil.

Yield 29%.

Δ IR (neat): 3600-3400, 1620, 1520, 1255, 1175, 1040, 845 cm NMR (CDCl 3): δ 0.88 (3H, d, J = 6 Hz), 0.90 (3H, d, J = 6 Hz), 1.2-1.7 (1H, m), 2.55 (1H, broad d, J = 5 Hz), 3.5-4.2 (5H, m), 3.77 (3H, s), 6.83 (2H, d, J = 109 Hz), 7.36 (2H, d, J = 9 Hz).

Example 112

In the same manner as in Example 13, 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone ethylene acetal was prepared as a colorless crystal from 2-hydroxy-1-15 (4-methoxyphenyl) -3-methyl-1-butanone ethylene acetal.

Yield 78%, m.p. 82-83 ° C.

IR (KBr): 1610, 1510, 1335, 1250, 1170, 1050, 970, 940, 930, 815 cm-1.

NMR (CDCl 3): δ 0.91 (6H, d, J = 7 Hz), 1.5-1.9 (1H, m), 2.99 (3H, s), 3.6-4, 2 (4H, m), 3.75 (3H, s), 4.67 (1H, d, J = 4 Hz), 6.83 (2H, d, J = 9 Hz), 7.34 (2H, d, J = 9 Hz).

Example 113 495 mg of 1- (4-methoxyphenyl) -2-methanesulfonyloxy-3-methyl-1-butanone ethylene acetal and 150 mg of calcium carbonate were heated at reflux for 148 hours in a mixture of 5 ml of water and methanol (3: 7 by weight). After conventional recovery and purification by column chromatography, 307 mg of 2-hydroxyethyl OC- (4-methoxyphenyl) isovalerate was obtained as a colorless oil.

Yield 81%.

IR (neat): 3600-3200, 1735, 1610, 1510, 1255, 1170, 1160, 1035, 830 cm-1.

35 NMR (CDCl 3): δ 0.70 (3H, d, J = 7 Hz), 1.03 (3H, d, J = 7 Hz), 2.0 - 2.5 (1H, m), 2, 27 (1H, broad s), 3.13 (1H, d, J = 10 Hz), 3.5-3.8 (2H, m), 3.76 (3H, s), 4.0-4, Δ (2H, m), 6.81 (2H, d, J = 9 Hz), 7.21 (2H, d, J = 9 Hz).

Il 51 7 5 3 3 6

Example 114 350 mg of 1-phenyl-2- (p-toluenesulfonyloxy) -1- (propanone dimethyl acetal and 0.20 ml of trimethylsilyl trifluoromethanesulfonate were stirred in 1 ml of ortho-5-acetic acid trimethyl ester for nine hours at 65 ° C. After the usual recovery, by gas chromatographic analysis as in Example 57 that the product was methyl α-phenylpropionate in 50.5% yield.

Example 115 In a similar manner to Example 58, α-phenylpropionate was prepared in 80% yield from 1-phenyl-2- (p-toluenesulfonyloxy) -1-propanone dimethyl acetate and ferric chloride.

Example 116 1- (6-Methoxy-2-naphthyl) -2- (1-O-camphorsulfonyl chloride and 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanodimethylacetate was prepared by the method of Example 80. 1-10-camphorsulfonyloxy) -1-propanodimethylacetal as a mixture of its two diastereomers. Mixture 20 was recrystallized from methanol to give another (m.p. 93-96 ° C, S <K 7p3-32.2 ° fc = 0.801, chloroform /) as colorless uniform crystals. The product obtained corresponded, in terms of IR and NMR spectra, completely to the 1- (6-methoxy-2-naphthyl) -2- (d-10-camphorsulfonyloxy) -1-propanonide-25-methylacetal diastereomer obtained in Example 80 + 32.5 ° fC = 1 , in roform /).

The starting compound 1-10-camphorsulfonyl chloride was prepared from commercially available ammonium 1-10-22 ° camphorsulfonate (& 7-> 18.4 [C = 5.3, water /) and thionyl chloride by the method described in H. Sutherland. , and RL Shriner, J. Am. Chem. Soc., 58 (1936) 62.

(δ) - 32.3 (C = 1.36, chloroform) m.p. 58-64 ° C.

52 75336

Example 117 555 mg of the diastereomer of 1- (6-methoxy-2-naphthyl) -2- (1-O-camphorsulfonyloxy) -1-propanodimethylacetal obtained in Example 116 was reacted as described in Example 5 to give 249 mg of methyl - (+) -? - (6-methoxy-2-naphthyl) propionate. Yield 96%, + 75.0 ° (C = 0.949, chloroform).

The IR and NMR spectra corresponded to those of the compound obtained in Example 56.

1 ° Example 118 799 mg of 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanonimethylacetal were dissolved in 3 ml of anhydrous pyridine, and the solution was stirred at room temperature. To the solution was added 833 mg of p-toluenesulfonyl chloride, followed by stirring at room temperature for another three days. Water (30 ml) was added to the mixture, which was then extracted three times in succession with 10 ml of methylene chloride. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the oily residue was purified by column chromatography (silica gel, methylene chloride) to give 1.019 g of 1- (6-raethoxy-2-naphthyl) -2- (p-toluenesulfonyloxy). propanone dimethyl acetal as a colorless oil. Yield 81.9%.

IR pure: 1612, 1489, 1360, 1278, 1192, 1178, 25 899, 560 cm -1.

NMR (CDCl 3): δ $ 1.13 (3H, d, J = 7 Hz), 2.40 (3H, s).

3.13 (3H, s), 3.21 (3H, s), 3.88 (3H, s), 5.04 (1H, q, J = 7Hz), 7.0-7.9 (10H , m).

Example 119 To a solution of 132 mg of sodium metal in 5 ml of anhydrous methanol was added 897 mg of 1- (6-methoxy-2-naphthyl) -2-bromo-1-propanone. The mixture was stirred at room temperature for seven hours, 20 ml of water was added thereto, and the resulting mixture was extracted three times with 10 ml of methylene chloride. Two drops of pyridine were added to the extracts, and the resulting mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 1- (6-methoxy-2-naphthyl) -2-hydroxy-1-propanone dimethyl acetal. The crude product was dissolved crude in 2 ml of anhydrous pyridine, and the resulting mixture was stirred at room temperature. To the solution was added 0.60 ml of benzenesulfonyl chloride, and the resulting mixture was stirred for another 20 hours. To the mixture was added 10 ml of water, followed by extraction three times with 10 ml of methylene chloride. The extracts were washed with 10 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the oily residue was purified by column chromatography (silica gel, methylene chloride) to give 1.024 g of 1- (6-methoxy-2-naphthyl) -2-benzenesulfonyloxy -propanone dimethyl acetal as a colorless oil. Yield 82.0% based on 1- (6-methoxy-2-naphthyl) -2-bromo-1-propanone.

IR pure: 1637, 1612, 1488, 1456, 1365, 1278, 1190, 925, 900, 761, 598 cm-1.

NMR (CDCl 3): δ 1.15 (3H, d, J = 7 Hz), 3.10 (3H, s), δ 3.18 (3H, s), 5.08 (1H, q, J = 7 Hz), 7.0 - 8.1 (11H, m).

Example 120 To 10 ml of methylene chloride was added 0.53 ml (0.75 g) of iodomethylsilane under argon and the resulting mixture was stirred at room temperature. A solution of 10 ml of anhydrous methylene chloride and 1.074 g of 1- (6-methoxy-2-naphthyl) -2- (p-toluenesulfonyloxy) -1-propanone dimethyl acetal was added to the mixture over 20 minutes, and the resulting mixture was stirred at the same temperature for a further 40 minutes. minutes. To the mixture was added 20 ml of a 20% aqueous sodium thiosulfate solution, and the resulting mixture was stirred overnight. The organic layer was washed five times in succession with 20 ml of 20% aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform) to give 495 mg of methyl α- (6-methoxy-2-naphthyl) propionate. Yield 81%. The NMR spectrum fully corresponded to the NMR spectrum of the compound obtained in Example 54.

Il

Claims (3)

Use of (2-hydroxy ketone acetals of Formula VI-1 OR 3 OH) 3. In 1 Ar - C-CH-R VI-1 in 4 OR 10 3 where Ar is 6-methoxy-2-naphthyl, 4-isobutylphenyl, 4-short-chain alkoxyphenyl, 4-difluoromethoxyphenyl, 2-thienyl, 4- (1-oxo-2-isoindolinyl) phenyl, 4-biphenyl or 4- (tert-butyl) -phenyl, and R 1 is hydrogen or a saturated aliphatic group, or Ar and R form a fused ring together With the carbon atoms to which they are attached, and R and R are independently alkyl groups or taken together form an alkylene group, in the preparation of an aromatic group substituted with an Φ-position aromatic group and their esters of the formula 1-2 R1 is Ar3-CH-COOR2 1-2 3 1 3 where Ar and R are as above, or Ar and R1 can form a fused ring together with the carbon atom to which they are attached and R is hydrogen, alkyl or hydroxyalkyl, wherein a compound of formula VI-1 is reacted with a compound of formula R5-SO2-Hal or (R5-SO2) wherein Hal is halogen and R3 is lower haloalkyl, phenyl, lower alkylphenyl, h allofenphenyl or d- or 1-campforyl, and a obtained Ot-sulfonyloxy ketone acetal of formula II-2