JPS603309B2 - 2-(2,2-dihalobinyl)thiophene and its manufacturing method - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula (In the formula, X is a halogen.

) and a method for producing the same. Although the compound represented by the general formula (1) is a new compound, it can be hydrolyzed or alcohololyzed under basic conditions and then subjected to acidic conditions to produce penicillin and cephalosporin. 2-thenyl acetic acid or its ester useful as a chemical modifier for talin [J. Amer. C
hem Sho, Ban, 2755 (1961)] [see reference example below].

The main conventional manufacturing methods for 2-thenyl acetic acid are roughly divided into the following three types depending on the raw materials used.

[112-chloromethylthiophene is treated with alkali cyanide to once form 2-cyanomethylthiophene,
Method of hydrolyzing this [M. J. Soyama al., M. C
．． Whada dford, Br.・I, 122.658 (19
68)]. ■ A method of converting 2-taacetothienone into 2-thhenylacetamide by Wmgemdt reaction with ammonium polysulfide and hydrolyzing this [0t■
Da blood, Ger. P. 832755 (1952)]. Leg (a) 2-thiophenaldehyde' A method of reacting an alkali cyanide with a chloroformic acid ester to form Q-alkoxycarbonyloxychenylacetonitrile, followed by catalytic reduction to form 2-cyanomethylthiophene, which is then hydrolyzed. [M. J. Soulal, M. 0. Wood
rd, Br. , 1, 122, 658 (1968)].
'b'2 There is a method in which a condensate of thiophenaldehyde and methyl methyl thiomethyl sulfoxide is treated with hydrogen chloride in alcohol to obtain 2-thenyl acetic acid ester, which is then hydrolyzed [Japanese Patent Publication No. 52-46063]. . However, in method '1', 2-chloromethylthiophene is unstable, explosive, and lachrymatory, making it difficult to handle. There are drawbacks such as the creation of ether. In method (2), during the production of the raw material 2-acetochenone, thiophene polymerization occurs due to the Lewis acid catalyst used, high temperature and high pressure conditions are required to carry out the Willgerodt reaction, and conditions are severe for the hydrolysis reaction. There are disadvantages such as requiring

In addition, the method [3}(a) has disadvantages such as the necessity of using a highly toxic cyanide compound, the necessity of using expensive reagents for catalytic hydrogenation, and the long reaction process. '3}
The disadvantages of this method include the need to handle strong-smelling sulfur compounds and the need to be careful about by-products. As a result of intensive studies on a method to overcome these drawbacks and selectively obtain only the target compound, the present inventors have found that the target compound can be obtained in good yield using thiophene and trihaloacetaldehyde as starting materials, both of which are easily available as industrial raw materials. The present invention was completed by discovering a method that can achieve a high yield.

The compounds of the present invention can be produced using the general formula (wherein R is hydrogen or an acyl group, and x is a halogen).

) It is an essential requirement to treat the Q-trihalomethyl-2-thiophenemetal derivative represented by the formula with a reducing agent. The compound of general formula (n) used as a raw material is a compound that can be easily produced by condensing thiophene with trihaloacetaldehyde, such as chloral, and treating with an acylating agent if necessary. Reducing agents used in the present invention include zinc or zinc-steel alloy and acetic acid, or hydrochloric acid or acetic acid-hydrochloric acid systems, metals such as sodium, magnesium, and aluminum, or amalgams thereof, and low-acid I-Q metal salts. For example, chromium(0)-salts, zinc chloride-phosphorus oxychloride-pyridine, which is a reagent for obtaining olefins from halohydrin derivatives, alkali metal salts such as sodium iodide and potassium iodide, and organic compounds such as butyllithium and phenyllithium. Examples include metal compounds, but zinc-acetic acid is preferably used because the reaction proceeds smoothly. In carrying out the reaction, it is not necessary to use a solvent, but if desired, ethers such as ether and tetrahydrofuran, hydrocarbons such as benzene and toluene/hexane, alcohols such as methanol and ethanol, or reducing solvents may be used. Acetic acid used as an agent may also be used as a solvent.

The reaction proceeds smoothly at room temperature to the reflux temperature of the solvent. The present invention will be explained in more detail with reference to Reference Examples and Examples below. Reference Example 1 Under an argon atmosphere, titanium tetraisopropoxide (15 mmol, 4.26 pm) is added to a 1 molar solution of titanium tetrachloride in methylene chloride (30 mmol, 30 mmol) under water.

After 1 minute, thiophene (2.52 hours, 30 mmol) is added.

Next, cool with ice water, add chloral (8.8
60 mmol) was added dropwise over a period of 10 minutes. After the dropwise addition was completed, the mixture was heated for 1 minute, and then water and methylene chloride were added to separate the organic layer. After washing with water, dry with anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure with a water stream, and the residue was distilled. Chloralisopropyl alcoholate was distilled out first, and then 5.0% of Q-trichloromethyl-2-thiophenemethanol was obtained. It was done. Yield: 72% (based on thiophene) Boiling point: 95-970/0.7 Hg (Literature value 140-14〆○/IQ yield Hg) Infrared absorption spectrum: 342 F 1065, 1044, 822, 71
Cucumber-1. Nuclear magnetic absorption spectrum (CDC13) 6:3
．． 48 (d, J = Z, IH), 5.40 (d, J = Z, IH), 6. Mottling ~7.50 (m, fine), Reference example 2 Literature [V. W. Floutz, J. Amer. Chem
S ratio. , 71, 2859 (1949)].
Q-Trichloromethyl-2-thiophene methanol (1
5.5 mmol, 67.1 Mmol) and acetyl chloride (15 mmol).
The mixture of step 5') was heated under reflux for 1 minute while stirring with a candle.

After acetyl chloride was distilled off under reduced pressure, the mixture was extracted with ether. The organic layer was washed with an aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off to obtain 2,2,2-trichloro-1-(2-thiophene)ethyl acetate (18.0 min, yield 97.8%) as white crystals. Reference example 3
Z methanol (85 skin) and sodium (
1.53 pm) was added to prepare a solution of sodium methoxide.

To this, 2-(2,2-dichlorovinyl)thiophene (3
．． 16.8 mmol) was added thereto, and the mixture was heated under reflux overnight. After confirming the disappearance of the raw materials by thin layer chromatography, hydrogen chloride gas was blown into the reaction solution while cooling with ice water to make it acidic, and the mixture was heated under reflux overnight. Methanol was removed under reduced pressure and extracted with ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated and the residue was distilled under reduced pressure to obtain 2.1 M of methyl 2-thenyl acetate with a boiling point of 109 to 11 ro/23 Hg. Yield: 80.
2% Nuclear magnetic absorption spectrum (CC14) 8:3.65 (s,
Pan), 3.70 (s, ga), 6,75-7.20 (m,
details). Example 1 Acetic acid 2,2,2-trichloro1-(
2-thiophene)ethyl (18) acetic acid (1)
Zinc powder (3 days) was added to the solution, and the mixture was heated under reflux while shaking vigorously.

Thereafter, zinc powder was added twice every hour for 3 days, and after 5 hours, the mixture was cooled to room temperature. Acetic acid was distilled off under reduced pressure, and the mixture was extracted with ether. It was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the activated carbon treatment, the crude crystals obtained by distilling off the solvent (10.8 pm, yield 91.5%) were distilled under reduced pressure to give 2-
9.23 tons of (2,2-dichlorovinyl)thiophene were obtained. When it was left still, it crystallized. Yield: 78.2% Melting point: mottled to 3 scales 0 Infrared absorption spectrum (NubI): 1605, 1510
, 1420, 1350, 13101282, 1245,
121fu1120107fu1050 91 ratione-1. Nuclear magnetic absorption spectrum (CDC13) 6:6.88-7.
30 (m, thin, ringH), 6.93 (s, IH, C
H=CC12). Calculated value as C6 day 4CI2S: C, 40.25: day, 2.25%. Measured value: C
, 40. Paper: Japan, 2.41%. Example 2
1Q-trichloromethyl-2-thiophenemethanol (300 days, 1.3 mmol)
was dissolved in acetic acid (3') and zinc powder (170 female, 2.
6 mmol) was added thereto, and the mixture was heated under reflux for 3 hours while stirring vigorously.

After cooling, water and ethyl acetate were added to separate the organic layer. The organic layer was washed successively with water, an aqueous sodium bicarbonate solution, and water, and dried over anhydrous magnesium sulfate. After filtration, concentrate and 20
An oily substance of 0x9 was obtained. Gas chromatography (2%
As a result of quantitative analysis using EGA, lm, 120q○), it was found that 2-(2,2-dichlorovinyl)thiophene was produced in a yield of 77%. Example 3Q-trichloromethyl-2-thiophenemethanol (300 females, 1
．． 3 mmol) in acetic acid (3) and zinc powder (
170-9, 2.6 mmol), sodium acetate (11
w9, 0.13 mmol) and heated to reflux while stirring vigorously.

After 4 hours, zinc powder (100 iso, 1.5 mmol) was added, and heating and refluxing was continued for an additional 3 hours.

After cooling, the mixture was treated in the same manner as in Example 2, and quantitative analysis by gas chromatography revealed that 2-(2,2-dichlorovinyl)thiophene was produced in a yield of 68%. Example 4 q-Trichloromethyl-bivalent thiophene methanol (3
000, 1.3 mmol) was dissolved in pyridine (50 mmol) and acetic anhydride (400 M) was dissolved while cooling with ice water.
added.

The mixture was gradually heated to room temperature, and after 2 hours, acetic acid (3 pieces) and zinc powder (9 of 170, 2.6 mmol) were added, and the reaction mixture was heated to reflux with vigorous stirring. After 2 hours, zinc powder (9 of 80, 1.2 mmol) was added, and after 3 hours more 9 of 80 was added.

Claims (1)

[Claims] 1. 2-(2,2-dihalobinyl)thiophene represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [In the formula, X is a halogen. ]. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The general formula is characterized by treating the α-trihalomethyl-2-thiophene methanol derivative represented by with a reducing agent ▲ Numerical formulas, chemical formulas, tables, etc. There is a method for producing 2-(2,2-dihalovinyl)thiophene represented by ▼ [wherein R is hydrogen or an acyl group,
is a halogen. ].