JPS5929192B2 - Method for producing α-thio-α-aromatic substituted propionate ester - Google Patents

Description

Detailed Description of the Invention The present invention relates to α-thio-α monoaromatic substituted propionic acid esters represented by the general formula (wherein R1 and R2 are alkyl groups which may be the same or different, and Ar is an aromatic is a group substituent.

). Many of the α-monoaromatically substituted propionic acids (wherein Ar is an aromatic substituent) represented by the general formula (wherein Ar is an aromatic substituent) obtained by desulfurization reduction and hydrolysis of the compound according to the present invention are used for pharmaceuticals and agricultural chemicals. It is useful as a fragrance, a fragrance, or an intermediate thereof.

For example, a series of compounds called prophene compounds are included in the general formula (2) and have remarkable anti-inflammatory, analgesic, and antipyretic effects. An example of this is when Ar is a 6-methoxy-1-cy-naphth-2-yl group, which is called naproxen and is currently widely used as a pharmaceutical. Conventional methods for producing naproxen can be roughly divided into the following three methods. (1) A method in which 2-acetyl-6-methoxynaphthalene is used as a raw material and a carbon-enriching reaction is carried out, using a ylide and a cyanating agent as a carbon-enriching agent (Japanese Patent Publication No. 48
-20545), a method using Wittig reagent (Japanese Patent Publication No. 52-31868), a method using potassium cyanide and ammonium carbonate (Japanese Patent Publication No. 47-7215), a method using methyl iodide after the Will-Geroth reaction (Japanese Patent Publication No. 48-1989).
702) etc.

(2) A method in which a rearrangement reaction is carried out using 2-ethylcarbonyl-6-methoxynaphthalene as a starting material, and thallium (e) nitrate is used as a reagent to facilitate two-transition (JP-A-50-4051, Kaisho 51-2324
9, JP-A-49-48648), a method using P-toluenesulfonyl azide (JP-A 53-15354), a method using diphenylphosphoric azide (DPPA) (JP-A 53-59238), etc.

(3) Treating 2-methoxynaphthalene and α-(P-toluenesulfonyloxy)propionic acid in the presence of aluminum chloride.

Method using Friedel-Crafts reaction (JP-A-54-
79258) etc. Among these methods, (
Method 1) uses relatively inexpensive reagents and has a good yield, and is considered to be the most excellent industrial production method.

However, the regioselectivity during the Friedel-Crafts reaction in which the starting material 2-acetyl-6-methoxynaphthalene is synthesized from 2-methoxynaphthalene and acetyl chloride is poor;
1-acetyl-2-methoxynaphthalene (4) represented by the following structural formula and 1-phthalene are produced as by-products.

Even if this regioselectivity is improved by using nitrobenzene as the acetyl J methoxyna solvent, the yield is very low, at most 43% (J.
Chemical Society 1 (0, 181 (1966); J
．． Chem. SOc. (1966)) has become a major drawback.

Method (2) also has problems, such as the fact that starting materials are difficult to obtain for the same reasons as method (1), and the method itself uses highly toxic thallium salts and expensive reagents.

Method (3) can be said to be an excellent method in that large blocks can be linked together at once, but the yield is extremely low due to lower reactivity and poorer regioselectivity than method (1). It has the disadvantage of being bad.

Even the improved method using nitrobenzene as a solvent has a very low yield of 32%. Thus, it can be seen that the Friedel-Crafts reaction to 2-methoxynaphthalene is the barrier for both methods.

Furthermore, if this Friedel-Crafts reaction can be improved, method (3) is considered to be advantageous over other methods in that it requires fewer steps. On the other hand, the present inventors
- Continued basic research on the Friedel-Crafts reaction of chlorosulfide [(a) Tetrahedron letter
Page 2183 (1975): TetrahedrOnLe
tt. , 2181 (1975), Pluchik Chemical Social Japan, Vol. 48, p. 3319 (1975)
);Bull,. Chem. SOc. Ja stop Nl483
3l9 (1975) etc.].

In recent years, efforts have been made to apply this reaction to the synthesis of prophene compounds. As a result, this α
- We have established an excellent method using the Friedel-Crafts reaction of chlorosulfide. The features of the Friedel-Crafts reaction using α-chlorsulfide are 2.
I can raise it.

When an aromatic compound and an alkyl halide are subjected to a Friedel-Crafts reaction in the presence of a Lewis acid, if the alkyl halide is substituted with an alkyl halide substituted with a sulfur atom at the α position (an example is α-chlorosulfide), the reactivity will increase first. This allows the reaction to proceed under milder reaction conditions, and secondly, regioselectivity increases. The aromatic substituted propionic acid of the general formula (2), which has become easily obtainable as a result of the present invention,
α-halopropionic acid ester represented by the general formula in which a sulfur atom is not substituted at the α-1 position (wherein, X is a halogen and R2 is an alkyl group).

) and an aromatic compound represented by the general formula, the reaction conditions are high temperature and for a long time, and the compound of the general formula (3) undergoes a dehydrohalogenation reaction. An acrylic ester represented by the general formula (wherein R2 is an alkyl group).

), and little or no of the desired α-monoaromatic substituted propionate ester is obtained.
The present inventors solved this serious problem by solving an α-chloro-α-thiopropionic acid ester represented by a general formula in which a sulfur atom is substituted at the α position (in the formula, R1 and R2 are alkyl which may be the same or different). The present invention was completed by solving the problem by improving the reactivity by using a group (which is a group). That is, as mentioned above, when Ar is a 6-methoxy-naphth-2-yl group, the general formula (2) is called naproxen. The two problems of α-
They found that this can be achieved by using chlorosulfide as one of the reagents, and established a new method using the α-chloro-α-thiopropionic acid ester of the present invention represented by the above-mentioned structural formula (5).

That is, by subjecting α-chloro-α-monothiopropionic acid ester represented by the above structural formula (5) to a Friedel-Crafts reaction with 2-methoxynaphthalene in the presence of a Lewis acid such as stannic chloride, a thio group is formed. The above structural formula without (
3) α-halopropionic acid ester and 2-
Compared to the reaction with methoxynaphthalene (see Comparative Example), the reactivity is greatly improved, and the regioselectivity is also greatly improved.
yl) propionic acid ester (Ar in the structural formula (1) above)
is a 6-methoxy-naphth-2-yl group) can be obtained at a high production ratio.

The final target product, naproxen, can be obtained by further reducing and desulfurizing this with Raney nickel or the like and hydrolyzing it. This new manufacturing route is summarized in the following equation.

The details of the reaction conditions of the above formula will be described below.

In the first step, an α-thiopropionic acid ester represented by the structural formula (6) (in the formula, R1 is an alkyl group, a phenyl group, and a benzthiazolyl group, and R2 is an alkyl group) is treated with a chlorinating agent. This is a step to obtain an α-chloro-α-thiopropionic acid ester represented by the structural formula (5) (in the formula, R1 and R2 are alkyl groups which may be the same or different). Possible chlorinating agents to be used include N-chlorosuccinimide, sulfuryl chloride, chlorine, chlorinated isocyanuric acid, iodobenzene dichloride, and sulfenyl chlorides. Sulfuryl chloride and chlorine are preferred because they are inexpensive and easily available as commercial reagents.

The amount of chlorinating agent to be used can be 1 to 5 equivalents, but 1.05 to 1.5 equivalents is preferred in order to ensure reaction without waste. As the solvent, it is preferable to use nonpolar solvents such as carbon tetrachloride, methylene chloride, chloroform, benzene, toluene, etc., but solvents other than extremely polar solvents and protic solvents can be used.

Moreover, it is also possible to use a mixture of these solvents as necessary. The reaction can be carried out at -10 to 30°C, and the reaction time becomes shorter as the reaction temperature is higher, but when the reaction is carried out at 20°C, it can be completed in 10 minutes to 2 hours.

Furthermore, since the reaction proceeds with a very high yield, if the residue of the chlorinating agent or the solvent does not participate in the reaction in the next step, it can be used as is in the next step. An example of this is when carbon tetrachloride or methylene chloride is used as a solvent and sulfuryl chloride or chlorine is used as a chlorinating agent. When the α-chloro-α-thiopropionic acid ester represented by the structural formula (5) of the present invention is isolated from the reaction solution under such conditions by operations such as filtration, vacuum concentration, and vacuum distillation, a base or It is important not to coexist with moisture or other nucleophilic reagents, and to keep the temperature at a high temperature of 30°C or higher, preferably 10°C or higher.

In the second step, α-chloro-α-thiopropionic acid ester represented by the structural formula (5) and the structural formula (4)
This is a step of treating an aromatic compound represented by the formula (1) in the presence of a Lewis acid to obtain an α-thio-α-monoaromatic substituted propionic acid ester represented by the structural formula (1).

The aromatic compound to be used is one having a high electron density, such as a substituted phenyl group in which Ar in the above structural formula (4) is represented by R-<○>- [R is an alkyl group having 1 to 4 carbon atoms, hydroxy group, an alkoxy group having 1 to 4 carbon atoms,
Amino group represented by phenyl group≧N- (R', R''
are alkyl groups having 1 to 4 carbon atoms which may be the same or different, or R' and R'5 may be bonded to form a 5- or 6-membered ring.

); Examples include groups.

The Lewis acids used are stannic chloride, titanium tetrachloride,
Examples include zinc bromide, ferric chloride, zinc chloride, etc., but stannic chloride is particularly preferred since it provides a high yield.

The amount of Lewis acid to be used can be 0.05 to 5 equivalents, but in order to carry out the reaction quickly and efficiently, it is possible to use 0.8 to 5 equivalents.
2.0 equivalents are preferred. As the solvent, solvents that are not directly involved in the reaction, such as carbon tetrachloride, methylene chloride, carbon disulfide, nitromethane, and nitrobenzene, can also be used.
It is also possible to use these as a mixed solvent if necessary. The reaction is possible in the temperature range of -10 to 50°C, but at low temperatures the reaction slows down, and at high temperatures α-chloro-α-thiopropionic acid ester represented by structural formula (5) undergoes a dehydrochlorination reaction. The temperature is preferably 0 to 35°C for reasons such as raising α-monothioacrylic acid ester.

Under these temperature conditions, the reaction is fully completed within 4 hours. Methods for reductive desulfurization after the completion of the second step include a method using activated nickel such as Raney nickel, zinc monoacetic acid,
Acrylic acid Examples include a method of forming an ester and then hydrogenating it.

Examples of reagents used for hydrolysis include aqueous solutions or water-alcoholic solutions of sodium hydroxide, potassium hydroxide, barium hydroxide, and the like. The present invention will be explained in more detail below using Examples, Comparative Examples, and Reference Examples. Example 1 (α-(ethylthio)-α-(6-methoxynaphtho-2)
Synthesis of ethyl propionate) α-chloro-α-
(Ethylthio)propionic acid 1.877 (1 equivalent) of ethyl and 1.507 (1 equivalent) of 2-methoxynaphthalene were dissolved in 20 ml of methylene chloride, and 2.657 (1. 1
equivalent amount) and stirred for 1 hour.

The mixture was separated by adding 20 y of water on an ice-water bath, washed with 10 y of water, and concentrated under reduced pressure to obtain 3.20 y of pale yellow oil. An analytical sample was obtained by dispersing this = portion using thin layer chromatography, and it was confirmed that the purity was 65% or more. NMR. IR. It was found by MS etc. that this product was ethyl α-(ethylthio)-α-(6-methoxynaphth-2-yl)propionate. Colorless oil NMR (CDCl3); δ1.12 (3H, .t17H
z), 1.24 (3H, .t17Hz), 1.86 (3
H1s), 2,50(2H,.dq13Hzand7H
z), 3.86 (3Hss), 4.23 (2H,.q1
7Hz), 6.9-7,9 (6H,.m). IR(Ne
at); 2950, 1715, 1600, 1382, 1
260, 1180, 1030, 852c7n-1MS (
m/e) , M+-318.1223 (calculated value Cl8H
22O3S-318.1228), 318(30), 2
58 (23), 257 (100), 245 (26), 1
83(50). Example 2 (α-(methylthio)-α-(6-methoxynaphtho-2)
Synthesis of ethyl α-(methylthio)propionate) 1.487 (1,05 equivalents) of ethyl α-(methylthio)propionate was dissolved in 8.07 carbon tetrachloride, and 1.487 (1.
After adding 16 equivalents of N-chlorosuccinimide in several portions while maintaining the temperature at 18 to 22°C, stirring was continued for an additional 1 hour and 30 minutes at the same temperature.

The reaction solution was quickly filtered and washed with 6.0y of carbon tetrachloride to remove the succinimide floating in the form of crystals. The thus obtained carbon tetrachloride solution of ethyl α-chloro-α-1(methylthio)propionate was prepared by dissolving 1.50 y (1 equivalent) of 2-methoxynaphthalene in 25 r of methylene chloride in advance and adding 2.5 y of stannic chloride. The mixture was added dropwise to a solution containing 65y (1.07 equivalents) while maintaining the temperature at 25 to 30°C. In the latter half of the dropping, foaming, which was thought to be caused by hydrogen chloride, was observed. After stirring at the same temperature for an additional 45 minutes after the dropwise addition,
Add 10ml of water to separate the layers, and wash the organic layer three times with water.
It was concentrated under reduced pressure. The obtained 2.75 tons of pale yellow oil was found to be mainly ethyl α-(methylthio)-α-1(6-methoxynaphth-2-yl)propionate. By separating a portion of this oily substance using thin layer chromatography, it was confirmed that the yield was 72% or more, and it was also used as an analysis sample. Boiling point: 164-168℃
/0.25mmHgNMR (CDCl3); δ1.27
(3H,.t17Hz), 1.88 (3H.s), 1.
97 (3H.s), 13.89 (3H,.s), 4
．． 27 (2H, .q17Hz), 7.05-7.95 (
6H,. m). IR (Neat); 2950, 1712
, 1620, 1595, 13801123011177
, 1100, 1027, 850CTL-1MS (m/e
); M+-304.1151 (calculated value Cl7H2OO3
S-304.1133), 304(13), 258(1
4), 257 (54), 256 (40), 211 (12
), 184(15), 183(100). Comparative Example 1 (Attempt to react ethyl α-bromopropionate and 2-methoxynaphthalene) Under the same conditions as Example 2, 2-
1.45y of methoxynaphthalene and 1.817y of ethyl α-bromo-propionate were dissolved in 107y of methylene chloride and 6y of carbon tetrachloride, and 2.67y of stannic chloride was added and stirred at 20°C for 26 hours, resulting in a Friedel-Crafts reaction. No product was obtained.

The mixture was further heated under reflux for 5 hours, but no reaction occurred. Example 3 (α-(methylthio)-α-(6-methoxynaphtho-2)
-Synthesis of ethyl propionate) 1.487 ethyl α-(methylthio)propionate was dissolved in 107 carbon tetrachloride, and 1.487 sulfuryl chloride was added dropwise at 10°C.
Stirred for 0 minutes.

This reaction solution was added at 5°C to a solution of 1.217% of 2-methoxynaphthalene dissolved in 137% of methylene chloride.
After adding 2.77 g of stannic chloride at ~10° C. and stirring for 40 minutes, 15 y of water was added to separate the liquids, and the liquids were separated twice with 10 g of water each. Concentration under reduced pressure gave 2.53y of yellow oil.
As a result of internal standard analysis using gas chromatography, the yield was 62.
α(methylthio)-α-(6-methoxynaphtho-2) in %
It was found that ethyl)propionate was obtained.
The physical property values were consistent with Example 2. Example 4 (α-(methylthio)-α-(6-methoxynaphtho-2
Synthesis of ethyl -yl)propionate) A carbon tetrachloride solution of ethyl α-chloro-α(methylthio)propionate (containing 1.487 ethyl α-chloro-α(methylthio)propionate) prepared in the same manner as in Example 2, A solution prepared by dissolving 0.767 g of 2-methoxynaphthalene in 11 y of nitromethane was added at 20 to 25° C., and 1.4 me of titanium tetrachloride was further added at the same temperature and stirred for 3 hours.

After washing twice with water, it was concentrated under reduced pressure to obtain 1.76 tons of orange oil. As a result of internal standard analysis using gas chromatography, it was found that ethyl α-(methylthio)-α-(6-methoxynaphth-2-yl)propionate was obtained in a yield of 25%. The physical property values were consistent with Example 2. Example 5 (A
When rH is 1-chloro-4-piperidinobenzene, α-
(Ethylthio)-α-(3-chloro-4-piperidinobuenyl)propionic acid synthesis) A carbon tetrachloride solution of ethyl α-chloro-α(ethylthio)propionate (α- Ethyl (ethylthio)propionate 1.641 t and N-chlorosuccinimide 1.47 t
was used.

) and 1.6% of 1-chloro-2-piperidinobenzene in advance.
2t and 2.67% of stannic chloride were dissolved in 207% of methylene chloride, and the mixture was added dropwise at 30° C. and stirred for 3 hours. water 6
After adding 0me and separating the layers, the aqueous layer was washed with 60 ml of 10% hydrochloric acid and about 42 y of 50% aqueous sodium hydroxide solution was added to PHll, extracted with toluene, washed with water, and further concentrated under reduced pressure to obtain 2.4 y of α-( A yellow oil containing ethyl ethylthio)-α-(3-chloro4-piperidinobuenyl)propionate was obtained. After further hydrolysis and extraction of acid components with alkaline water, the pH was adjusted to approximately 5 with hydrochloric acid water and extracted with toluene. This was concentrated under reduced pressure to obtain a 0.13V pale yellow oil. G after the grudge and diazomethane treatment of this
From C-MS, α-(ethylthio)-α-(3-chloro-
It was found that 4piperidinobuenyl)propionic acid was obtained. NMR (CDCl3); δ1.25 (3Hs
t17Hz), 1.55-1.8 (6H,.m), 2.
85-3.1 (4H1m), 2.35 (2H.q, 7H
z), 6.9-7.5 (3H,.m) MS (m/e);
343 (4), 341 (13, M+), 283 (6),
282 (36), 281 (18), 280 (100),
220(4) Example 6 (When ArH is anisole:
Synthesis of ethyl α-(ethylthio)-α-(4-methoxyphenyl)propionate) Carbon tetrachloride solution of ethyl α-chloro-α(ethylthio)propionate prepared in the same manner as in Example 2 (α-( 0.16y of ethyl thio)propionate and 0.14y of N-chlorosuccinimide were used.

) was added with 10 r of methylene chloride and 1.0 V of anisole, and then 0.3 y of stannic chloride was added at 20°C and stirred for 1.5 hours. Water and toluene were added to this to separate the layers, and the resulting pale yellow oil was washed with water and concentrated under reduced pressure. The resulting pale yellow oil was fractionated using thin layer chromatography to obtain a colorless oil with a size of 0.177.
This second meeting, IR. It was found by MS etc. that it was ethyl α-(ethylthio)-α-(4-methoxyphenyl)propionate. NMR (CDCl3); δ1
．． 13 (3H, .t, 7Hz), 1.25 (3H, .t
17Hz), 1.78 (3H,.2s), 2.47 (2
H,. q17Hz), 3.78 (3H1s), 4.22
(2Hsq17Hz), 6.87 (2H1d110Hz
), 7.40 (2H, .d110Hz). IR(Nea
t); 1718, 1602, 1505, 1250111
85, 1100, 1035, 5830cwL-1M
S (m/e); M+-268.1121 (calculated value Cl4
H2OO3S=268.1131), 268(13),
208 (19), 207 (100), 206 (29),
195 (28), 161 (10), 134 (16), 5
133(68). Example 7 (When ArH is anisole: α-(methylthio)-α
Synthesis of ethyl-(4-methoxyphenyl)propionate) Add 10% methylene chloride to a carbon tetrachloride solution of ethyl α-chloro-α-(methylthio)propionate obtained in the same manner as in Example 3. and added anisole 1.08f7,
Furthermore, 2.67 stannic chloride was added at 20° C., and the mixture was stirred for 1.5 hours.

After washing with water, toluene and water were added to separate the layers, which was further washed with water and concentrated under reduced pressure to obtain a nearly colorless oil of 1.95 f. GC revealed that this product was almost pure ethyl α-(methylthio)-α-(4-methoxyphenyl)propionate. Yield about 77%. A portion of this was taken and further fractionated using thin layer chromatography to obtain an analytical sample. NMR (CDCl3): δ1.25 (3H
、． t17Hz), 1.77 (3H,.s), 1.97
(3H,.s), 3.77 (3H18), 4.23 (2
Hsq17Hz), 6.86 (2H,.d110Hz)
．． 7.40 (2H, .d110Hz), IR (Neat
): 1715, 160011505, 1245, 118
5, 1180, 1030, 830CIrL-1MS (m
/e); M+=254.0977 (calculated value Cl3Hl8
O3S=254.0976), 254(11), 208
(15), 207 (100), 206 (30), 181
(29), 134(16), 133(67). Example
8 (When ArH is thiophene: Synthesis of ethyl α-(methylthio)-(2-thienyl)propionate) The carbon chloride solution was mixed with a previously prepared methylene chloride solution containing 0.5r of thiophene.
In addition to 5y, add 2.6y of stannic chloride to 15 to 20%
It was added at ℃ and stirred for 1 hour.

After washing with 10 ml and 5 ml of water, it was concentrated under reduced pressure and
．． 57 brown oil was obtained. A portion of this was fractionated by thin layer chromatography, and the obtained pale yellow oil was used as an analysis sample. From the analysis of this product, it was found to be ethyl α-(methylthio)-α-(2-thienyl)propionate. NMR (CDCl3); δ1.30 (3H,.t
,7Hz), 1.92(3H,.s), 2.05(3H,.s)
、． s), 4.23 (2H,.q17Hz), 6.75
~7.35 (3H1m)・IR (Neat); 1718
, 1250, 1230, 1108, 702C! ! L-1
MS (m/e): M+=230.0393 (calculated value Cl
OHl4O2S2-230.0433), 230(19
), 185(16), 184(34), 183(17)
, 159(11), 157(87), 137(36),
109(45). Example 9 (When ArH is phenol: α-(methylthio)-α
Synthesis of ethyl mono(4-hydroxyphenyl)propionate) α-chloro-α-(
A solution of ethyl methylthio)propionate in carbon tetrachloride,
Add a solution of 1.07 phenol dissolved in 10 ml of methylene chloride, and add 2.61 ml of stannic chloride. was added at 20°C and stirred for 3 hours.

After adding water and separating the liquid, water and toluene were added to separate the liquid, which was further washed with water and concentrated under reduced pressure to obtain a pale green oil of 2.547. This product was found by Hatakeho et al. to be almost pure ethyl α-(methylthio)-α-(4-hydroxyphenyl)propionate. It was further purified using thin layer chromatography and used as an analytical sample. Colorless oil NMR (CDCl3); δ1.27 (3H,.t, 7H
z), 21.78 (3H,.s), 4.24 (2H,.s).
q17Hz), 6.2 (1H, .br0ad, .s),
6.80 (2H, .d19Hz), 7.34 (2Hsd
, 9Hz). IR (Neat); 327011715,
169011605, 1505, 1240, 1100,
21015, 835CfL-1MS (m/e); M
+=240.0798 (calculated value Cl2Hl6O3S-2
40.0818), 240(26), 194(23),
193 (100), 192 (24), 167 (80),
147(16), 119(44). 3 Comparative example 2 (α-
Attempt to react ethyl bromopropionate with phenol)
As the same conditions as in Example 9, phenol was 0.94? and 1.813 t of ethyl α-bromopropionate were dissolved in 107 methylene chloride and 67 carbon tetrachloride, and 2.6 y of stannic chloride was added and stirred at 20°C for 26 hours. Ethyl (4-hydroxyphenyl)propionate or ethyl α-(2-hydroxyphenyl)propionate) was not obtained.

The mixture was further heated under reflux for 5 hours, but no reaction occurred. Example 10 (When ArH is isobutylbenzene; Synthesis of ethyl α-(methylthio)-α-(4-isobutylphenyl)propionate) α-chloro-α-(methylthio) prepared in the same manner as in Example 3 Add a solution of ethyl propionate to carbon tetrachloride, add 1.5r of isobutylbenzene to 88g of methylene chloride.
In addition to the solution dissolved in 7, add 2 stannic chloride at 15℃.
．． 67 was added and stirred for 1 hour.

Add 20ml of water and separate the liquid, then add toluene and water,
After removing hardly soluble substances, the liquid was separated and concentrated to obtain 0.60 t of yellow oil. A portion of this was purified by thin layer chromatography to obtain an analytical sample of ethyl α-(methylthio)-α-(4-isobutylphenyl)propionate. It was a colorless oil. NMR (CDCl3); δ0.90 (
6H. d17Hz), 1.26 (3H,.t17Hz)
, 1.78 (3H.s), 1.98 (3H.s), 1.
6-2.3 (1H, m), 2.45 (2H, .d17H
z), 4.24 (2H1q, 7Hz), 7.13 (2H
、． d, 9Hz), 7.37 (2H, .d19Hz).
IR (Neat); 2920, 1715, 123011
10011018C-JMoV! -1MS (m/e); M+
=280.1474 (calculated value Cl6H24O2S=28
0.1494), 280(3), 234(10), 23
3 (63), 208 (21), 207 (100), 20
5(11). Example 11 (When ArH is biphenyl: α-(methylthio)-α
Synthesis of ethyl-(4-phenylphenyl)propionate) A carbon tetrachloride solution of ethyl α-chloro-α(methylthio)propionate prepared in the same manner as in Example 3 was prepared by dissolving biphenyl 1.4f7 in methylene chloride 10y. In addition to the liquid, 2.67 g of stannic chloride was further added at 20° C. and stirred for 1 hour.

After treatment and concentration in the same manner as in Example 10, a yellow oil of 1.8f7 was obtained. A portion of this was purified by thin layer chromatography to obtain an analytical sample of ethyl α-(methylthio)-α-(4-phenylphenyl)propionate. It was a pale yellow oil. NMR (CDCl3); δ1.29 (3H,
．． t17Hz), 1.83(3H,.s), 2.03(
3H,. s), 4.27 (2H,.q17Hz), 7.
2-7.8 (9H1m)・MS (m/e); 300 (1
6, M+), 254 (21), 253 (100), 22
7(63), 53(45). Example 12 (Synthesis of ethyl α-(isopropylthio)-α-(6-methoxynaphth-2-yl)propionate) In place of 1.48f1 of ethyl α-(methylthio)propionate in Example 3, α-( Ethyl isopropylthio)propionate 1
．． A similar reaction was carried out using 867 to obtain a reddish-orange oil with a voltage of 3.37V.

As a result of gas chromatography analysis, the yield was 45%, α(isopropylthio)-α-(6-methoxynaphtho-
It was found that ethyl 2-yl)propionate was obtained. A portion of this was separated using a thin layer chromatograph 1-1 to obtain an analytical sample. Colorless oil NMR (CDCl3); δ1.13-1.36 (9H,
．． m), 1.93 (3H,.s), 2.92 (1H,.
septet1J=8Hz), 3.88(3H,.s)
, 4.26 (2H12q,.J=8Hz), 7.09~
7.86 (6H,.m). IR(Neat);2960
, 1720, 16001123011180, 1100
1103018500! n-1MS (m/e); 332
(M+, 9), 259 (20), 2258 (23), 2
57 (100), 256 (11), 185 (11), 1
84(10), 183(36). Example 13 (ArH
When is anisole: α-(methylthio)-α-(4-
Synthesis of ethyl methoxyphenyl)propiotriphosphate) In place of 2.67 stannic chloride in Example 7, 1.36 r of aluminum chloride was used for the same reaction to obtain 2.87 as a pale pink oil.

α with a yield of 50% by gas chromatography
-(methyl 3thio)-α-1(4-methoxyphenyl)
It was found that ethyl propionate was obtained. Example 14 (When ArH is anisole: α-(methylthio)-α
-Synthesis of ethyl (4-methoxyphenyl)propiotetraphosphate) A reaction was carried out in the same manner using 1.9f of titanium tetrachloride in place of 2.6y of tin chloride in Example 7, and 2.527% of the colorless oil was obtained. I got something.

α-(Methylthio)-α-(4-methoxyphenyl) in 80% yield by NMR and gas chromatography.
It was found that ethyl propionate was obtained. Example
15 (When ArH is 1-chloro-2-methoxynaphthalene: Synthesis of ethyl α-(methylthio)-α-(5-chloro-6-methoxynaphth-2-yl)propionate) In the same manner as in Example 3. The prepared carbon tetrachloride solution of ethyl α-chloro-α-(methylthio)propionate was added to a solution of 1.35f7 of 1-chloro-2-methoxynaphthalene and 4.95y of titanium tetrachloride dissolved in 10y of methylene chloride for 20~ It was added at 25°C and stirred for 3.5 hours.

Water was added under ice-water cooling to separate the layers, which was further washed with water and then concentrated under reduced pressure to obtain a yellowish brown oil with a compound size of 2.647. It was found that ethyl α-(methylthio)-α-(5-chloro-6-methoxynaphth-2-yl)propionate was obtained by chromatography and gas chromatography in a yield of 70%. An analytical sample was obtained by fractionating a portion of this using thin layer chromatography. Yellow oil NMR (CDCl3); δ1.28 (3H.t,.J=
7Hz), 1.88 (3H,.s), 1.98 (3H1
s), 3.99 (3H,.s), 4.28 (2H.q1
J=7Hz), 7.2-8.25 (4H,.m). IR
(Neat);172011600, 1275, 107
5, 755 (1771-1MS (m/e); 340 (1
1), 388 (M+28), 293 (33), 292 (
29), 291 (100), 290 (36), 267 (
12), 265 (34), 219 (19), 217 (4
4). Reference Example 1 (Synthesis of ethyl α-(6-methoxynaphth-2-yl)propionate) 0.187 ethyl α-(methylthio)-α-(6-methoxynaphth-2-yl)propionate was added to 6 ml of ethyl alcohol. Dissolved in
Add 2.0 ml of Raney nickel suspension (NDHT9O manufactured by Kawaken Fine Chemical Co., Ltd., whose solvent was replaced with ethyl alcohol in advance), stir at 40°C for 30 minutes, filter, wash with toluene 3 times, and wash once with water. , and one time of toluene washing.

The obtained ▲ washing liquid was separated, and the toluene layer was concentrated under reduced pressure to a 0.
A nearly colorless oil of 157 was obtained. This thing is IR
．． It was found by MS etc. to be ethyl α-(6-methoxynaphth-2-yl)propionate. It also solidified when left standing. Yield 95% o Melting point 50-52℃ Boiling point 149℃/0.2m77! Hg NMR (CDCl3); δ1.19 (3H.t, 7Hz
), 1.56 (3H, .d17Hz), 3.83 (1H
1q17Hz), 3.88 (3H,.s), 4.12 (
2H1q17Hz), 6.9-7.8 (6H,.m).
IR (KBr); 2955, 1722, 1600111
83, 1160, 1030, 860, 823, 480 (
1-JMoV! -1MS (m/e); M+-258, 129
1 (calculated value Cl6Hl8O3-258.1256), 2
58(100), 186(22), 185(76) Reference Example 2 (Synthesis of ethyl α-(6-methoxynaphth-2-yl)propionate) α-(methylthio)-α-(6-
Ethyl methoxynaphth-2-yl)propionate 0.1
87, acetic acid 2.07, zinc powder 0.147, anhydrous copper sulfate 0
．． 01y was added and the mixture was heated under reflux for 2 hours.

After acetic acid was distilled off under reduced pressure, 5y of water and 207 ml of toluene were added to separate the layers, washed with water, and the toluene was distilled off under reduced pressure to obtain 0.14
7 was obtained as a colorless oil. This one is NMR. IR. M.S.
It was found to be ethyl α-(6-methoxynaphth-2-yl)propionate. The yield was 90%, and the physical properties were the same as in Reference Example 1. Reference example 3 (α1 (6
-Synthesis of ethyl methoxynaphthiopropionate) α-(methylthio)-α-(6-methoxynaphtho-)
Dissolve 0.18f7 of ethyl (2-yl)propionate in 4ml of dimethylformamide, and dissolve 0.18f7 of ethyl (2-yl) propionate in 4ml of dimethylformamide, and dissolve
:1) Solution (add 0.067 ml of metallic sodium to 4 ml of ethyl alcohol and react, then 0.20 methyl mercaptan
7 and further added 4 ml of dimethylformamide) at room temperature, and the mixture was stirred for 1 hour.

After further heating to 60°C and stirring for 30 minutes, cool it,
87 y of water, 2.5 y of hydrochloric acid, and 5 y of toluene were added to separate the layers, and the mixture was washed twice with water. Concentrate toluene under reduced pressure to obtain 0 yellow oil.
．． Obtained 14y. This one is NMR,. IR,. MSl
It was found to be ethyl α-(6-methoxynaphth-2-yl)propionate. The yield was 90% and the physical properties were the same as in Reference Example 1. Reference example 4 (α1(6-
Synthesis of ethyl methoxynaphth-2-yl)propionate) α-(methylthio)-α-(6-methoxynaphtho-2-yl)
-yl) ethyl propionate 0.56y to acetic acid 6m13
Dissolved in 1% acetic acid solution of hydrogen peroxide (a solution prepared from 1ml of 30% hydrogen peroxide and 31ml of acetic acid) 6
．． Add 9 ml of
Stir for hours.

After adding and separating 20 ml of chloroform and 20 ml of water,
The mixture was washed four times with 20 ml of water each time, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow oil with a yield of 0.717. By distilling this oil under reduced pressure while heating, 0.4
27 A pale yellow oil was obtained. This one is NLIR,. M.S.
It was found to be ethyl α-(6-methoxynaphth-2-yl)acrylate. Yield 88% Melting point; 5
9~62℃ Boiling point; 152~175℃/0.1~0.15mmHgN
MR (CDCl3); δ1.32 (3H, .t17Hz
), 3.91 (3H.s), 4.33 (2H.q, 7H
z), 6.00 (1Hss), 6.40 (1H,.s)
, 7.0-8.0 (6H,.m). IR(Neat);
1713, 1623, 1600, 1260112201
118011035? -1MS (m/e); M+-25
6.1088 (calculated value Cl6Hl6O3 - 256.10
98) This compound was further dissolved in 10 ml of ethyl alcohol, 6.2 ml of Raney nickel suspension (NDHT-90 manufactured by Kawaken Fine Chemical Co., Ltd., whose solvent had been replaced with ethyl alcohol in advance) was added, and the mixture was heated under a hydrogen atmosphere at room temperature for 3 hours.
The mixture was stirred at 40°C for 1 hour.

Decanted and washed twice with 20 ml of toluene, combined and concentrated under reduced pressure, then 40 ml of toluene and 10 ml of water.
was added to separate the layers, and the mixture was washed twice with 10 ml of water each time. A colorless oil of 0.365y obtained by concentration under reduced pressure solidified upon standing. What about this thing? M. IR,. α1 (from MS etc.
It was found to be ethyl 6-methoxynaphth-2-yl)propionate. The yield was 86%, and the physical properties were the same as in Reference Example 1.

Reference Example 5 (Synthesis of α-(6-methoxynaphth-2-yl)propionic acid) 0.95V of ethyl α-(6-methoxynaphth-2-yl)propionate was mixed with 3 ml of ethyl alcohol.
．． Dissolved in 0y, water 1.0V) Sodium hydroxide 0.1
6y was added and heated under reflux for 15 minutes.

Add 2V of water and 5V of toluene to separate the layers, add toluene (15V) and 1.35f7 of concentrated hydrochloric acid to the resulting aqueous layer, separate the layers at 70°C, wash with water, and concentrate under reduced pressure to form almost colorless crystals of 0.80y. I got it. Yield 95%. This product was recrystallized once with toluene and used as an analysis sample. The physical properties of this product were as follows, and were in good agreement with the standard product of α-(6-methoxynaphth-2-yl)propionic acid.

Melting point: 156.8-157.3°C NMR (CDCl3): δ1.57 (3H, d) 7
Hz), 3.83 (IH,.q) 7Hz), 3.86
(3H)s), 6.9-8.05 (6H,.m)
, 8.0(IH)BrOad,. s). Engineering R (KBr); 2930) 1690, 1595,
1380) 1260) 1223, 1027, 920
) 853, 820) 673, 480CffL-1MS
(m/e); 230 (93, M+), 185 (
100). Reference example 6 (α-(5-chloro-6-methoxynaphtho-2
-Synthesis of ethyl propionate) α-(methylthio)-α-(5-chloro-6-methoxynaphtho-
After adding 10y of acetic acid, 1.7V of zinc powder and 0.2V of copper sulfate to 2.5V of ethyl 2-yl) propionate,
The mixture was heated under reflux for 1 hour.

After adding water and toluene to remove insoluble materials, the mixture was separated and washed with water. Toluene was distilled off under reduced pressure, leaving a pale red oil with a concentration of 1.94 g.
I got f7. NMR and gas chromatography revealed that ethyl α-(5-chloro-6-methoxynaphth-2-yl)propionate was obtained in a yield of 95%. A portion of this was collected using thin layer chromatography to obtain a sample for analysis. Colorless crystal melting point; 53.5-55℃ NMR (CDCl3): δ1.18 (3H,.t,J
=7Hz), 1.56(3H,.d,.J=7Hz
), 3.84 (IH.q,.J=7Hz), 3.96
(3H)s), 4.11(2H,.q,.J=7H
z), 7.1~8.2 (5H,.m)・Eng R (KBr); 1720) 1600) 1275,
1180, 1160) 1070N800cwL-1M
S (m/e); 292 (M+), 219, 194.

Claims (1)

[Claims] 1 α-chloro-α-thiopropionic acid ester represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^1 and R^2 may be the same or different) ) and aromatic compounds represented by the general formula ArH [where Ar is a substituted phenyl group represented by ▲ mathematical formula, chemical formula, table, etc. ▼ {R is an alkyl group having 1 to 4 carbon atoms] group, hydroxy group, alkoxy group having 1 to 4 carbon atoms, phenyl group, ▲numerical formula, chemical formula, table, etc.Amino group represented by ▼ (R', R'' may be the same or different and have 1 carbon number) ~4 alkyl group, or R' and R'' may be combined to form a 5- or 6-membered ring. ), X is hydrogen or a halogen element}, ▲ mathematical formula, chemical formula,
There are tables etc. 6-methoxy-naphtho- represented by ▼
2-yl group (X' is hydrogen or halogen element), and ▲
There are mathematical formulas, chemical formulas, tables, etc. It is a 2-thienyl group represented by ▼. ] in the presence of a Lewis acid (in the formula, R^1 , R^2, and Ar are the same as above.). 2 α-thiopropionic acid ester represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^
1. R^2 is an alkyl group which may be the same or different. ) with a chlorinating agent in the presence of a non-polar solvent. ^1 and R^2 are alkyl groups which may be the same or different. There are chemical formulas, tables, etc. Substituted phenyl group represented by ▼ {R is an alkyl group with 1 to 4 carbon atoms, hydroxy group, alkoxy group with 1 to 4 carbon atoms, phenyl group, ▲ Numerical formulas, chemical formulas, tables, etc. There is an amino group represented by ▼ (R' and R'' are alkyl groups having 1 to 4 carbon atoms, which may be the same or different, or R' and R'' are bonded to form a 5- or 6-membered ring. ), X is hydrogen or halogen element}, ▲ mathematical formula, chemical formula,
There are tables etc. 6-methoxy-naphtho- represented by ▼
2-yl group (X' is hydrogen or halogen element), and ▲
There are mathematical formulas, chemical formulas, tables, etc. It is a 2-thienyl group represented by ▼. ] in the presence of a Lewis acid (in the formula, R^1 , R^2, and Ar are the same as above.). 3. The method according to claim 1, wherein the Lewis acid is stannic chloride, titanium tetrachloride, zinc bromide, and ferric chloride. 4. The method according to claim 2, wherein the Lewis acid is stannic chloride, titanium tetrachloride, zinc bromide, and ferric chloride. 5. The method according to claim 2, wherein the chlorinating agent is N-chlorosuccinimide, sulfuryl chloride, chlorine, and chlorinated isocyanuric acid. 6. The method according to claim 2, wherein the temperature of the chlorination reaction and the isolation operation of the α-chloro-α-thiopropionic acid ester is -10 to 30°C.