JPS62205038A - Production of 4-fluoro-1-butene derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a raw material for drugs and agricultural chemicals, by reacting a cyclopropane alkanol derivative or cyclopropane ketone derivative as a raw material with a hydrogen fluoride- amine complex as a fluorinating agent. CONSTITUTION:A cyclopropane derivative (e.g. cyclopropylphenyl methanol, etc.) shown by formula I (R1 is H, alkyl or phenyl; R2 is H or hydrocarbon) is reacted with a hydrogen fluoride-amine complex (e.g. hydrogen fluoride- melamine complex, etc.) to give a 4-fluoro-1-butene derivative (e.g. 4-fluoro-1- phenyl-1-butene, etc.) shown by the formula II. EFFECT:Obtainable in high yield by a simple operation.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing 4-fluoro-1-butene derivatives useful as raw materials for pharmaceuticals and agricultural chemicals.

[Prior art] 4-Fluoro-1-butene derivatives have conventionally been produced using the corresponding direct alcohol or halides such as chloride and bromide as starting materials, which are then reacted with a 7-fluorinating agent to produce 4-fluoro-1-butene derivatives. Wittig's method for the carbonyl compound of 3-fluoropropylenephosphorane
g) It is synthesized by a method such as a type reaction. However, such a reaction has problems in that the reactants used are expensive and the synthesis of starting materials is difficult.

On the other hand, a method is known in which a 4-bromo-1-butene derivative is synthesized by using cyclopropyl alkanol as a starting material and reacting it with hydrobromic acid. This method is industrially advantageous because inexpensive raw materials can be used and the number of steps is small (the yield is good, and cyclopropyl alkanols with various substitution forms can be easily permeated, but hydrogen bromide Even if a similar reaction is carried out using 7) hydrohydric acid instead of the acid, no 4-fluoro-1-butene derivative is produced. In other words, due to the low reactivity of fluorine anions, hydrofluoric acid acts only as an acid catalyst;
This is because it only contributes to the cleavage of the cyclopropane ring and does not cause fluorination.

[Problem that the invention seeks to solve]

Therefore, an object of the present invention is to provide a method for effectively producing a 4-fluoro-1-butene derivative using a cyclopropane alkanol derivative or a cyclopropane ketone derivative as a raw material.

[Means for solving problems]

The present invention was made based on the knowledge that the above problems can be effectively solved by using a hydrogen fluoride-amine complex as a fluorinating agent.

That is, the present invention provides a cyclopropane represented by the general formula (I): (wherein R1 is hydrogen, an alkyl group, or a phenyl group, R2 is a hydrocarbon group, and R5 is hydrogen or a hydrocarbon group) General formula (■) characterized by reacting a derivative with a heptahydrogen fluoride-amine complex: 4-fluoro-1 represented by (wherein R,, R2 and R1 have the same meanings as above) - Provides a method for producing a butene derivative.

The starting material used in the present invention, the compound represented by general formula (1), is easily synthesized from the corresponding allyl alcohol. In the present invention, in the general formula (r), R1 is preferably hydrogen, an alkyl group having 1 to 10 carbon atoms, or a phenyl group, and these groups may have a substituent. Among these, hydrogen, methyl group, and phenyl group are particularly preferable as R1.

In the formula, R2 is preferably an alkyl group having 1 to 12 carbon atoms, an alkenyl group, an alkynyl group, a phenyl group, a benzyl group, a 7-enethyl group, or a styryl group, and R5 is hydrogen or an alkyl group having 1 to 4 carbon atoms. An alkyl group, an alkenyl group having 2 to 8 carbon atoms, or an alkynyl group is preferred.

In the present invention, the above compound (I) is reacted with a hydrogen fluoride-amine complex to open the three-membered ring and introduce fluorine. Examples of the hydrogen fluoride-amine complex used here include a hydrogen fluoride-melamine complex and a hydrogen fluoride-pyridine complex.

In the present invention, these amine complexes are preferably used in large excess, preferably 10 equivalents or more, relative to the raw material compounds, and the reaction is preferably carried out at a temperature of 0 to 25°C for 5 minutes to 1 hour. At this time, it is preferable to carry out the reaction without a solvent or using various solvents such as engineered tyl ether, chlorobenzene-diisopropylamine mixed solvent, etc. in a nitrogen stream. In addition, an alkali metal hydrofluoride salt can be added to the reaction system in order to remove water in the reaction system and increase the nucleophilicity of fluorine ions. Potassium fluoride or the like can also be added to the system to precipitate any hydrogen fluoride present as potassium hydrofluoride.

In the present invention, after the reaction, the product is separated by a conventional method.

〔Effect of the invention〕

According to the present invention, 4-fluoro-1-
Butene derivatives can be produced in high yield.

Next, the present invention will be explained with reference to examples.

〔Example〕

Example 1 In a 30rB1 polyethylene centrifuge tube under a nitrogen atmosphere,
After adding 78 mg (1 mmol) of hydrium hydrogen fluoride and 74 mg (0.5 mmol) of cyclopropylphenylmethanol, 1.0 ml of chlorobenzene (0.3 mmol) was added. After cooling to ℃, the anhydrous hydrofluoric acid-pyridine complex was prepared.
l! (Hydrofluoric acid/pyridine-7/3v/v) was added. After stirring this mixed solution at 0° C. for 5 minutes, 4 mf of a 15% aqueous potassium fluoride solution was added.

After extracting this mixed solution with ether (10 mj x 3 times), the ether layer was extracted with saturated sodium bicarbonate solution (20 mj), saturated saline solution (
20m), and concentrated after drying with anhydrous sodium sulfate. The resulting reaction mixture was passed through a silica gel column (solvent: n
- Purified with hexane/ethyl acetate = 20/1), 4-
54.8 mg (yield 73%) of fluoro-1-phenyl-1-butene was added.

Product identification data is shown below.

NMR (C-port α3): δ2.60 2Hd, d, t 24. OHz
5.66.5.67δ4.49 2Hd,t
47JHz 5.66δ6.15 1t
l d, t 16.4 5.67δ0.
49 ill d 16.4δ
7. O-7,4511m IR(neat) 3040.2910.1595.1490.1445,
965,745.690 Example 2 Examples were carried out by variously changing the solvents chlorobenzene (Pb0) and diisopropylamine ((i Pr) 2N11) used in Example 1 and the additive potassium hydrofluoride (KF-HF). The reaction was carried out in the same manner as in 1. The obtained results are shown in Table 1 along with the solvents and additives used.

Table 1 Example 3 In a nitrogen atmosphere, 78 mg (1.0 mmol) of potassium hydrogen fluoride and 1.0 m of tetrahydrofuran were placed in a 30 ml polyethylene centrifugal tube, and after cooling to 0°C, anhydrous hydrofluoric acid-pyridine complex was prepared. 1.0 ml (hydrofluoric acid/pyridine = 7/3 v/v) was added.

After stirring for 10 minutes, 1.0-liter of a tetrahydrofuran solution containing 102 mg (0.5 mmol) of 1-()lans-2'-7enylcycloprobyl)-pentanol was added. This mixed solution was stirred at room temperature for 30 minutes to react, and then subjected to the same post-treatment as in Example 1, resulting in 73 mg of l-fluoro-1-phenyl-3-octene (yield: 71
%) was obtained.

Product identification data is shown below.

NMR (C mouth α): δ=0.83 311 t 6.12δ=1
．． 0-1.5 411 m δ=1.8-2, 1 28 m δ=1.3-1.8 211 m δ=5J6 211 ddd 46.8 7.
2 6.1δ=5J-5,52Fl m δ=7.1-7,4 58 m In (neat) 2900.2800.1490.1445,965,7
50.695 Example 4 A reaction was carried out in the same manner as in Example 1 using various starting materials. Table 2 shows a summary of the raw materials used and the yields of the products.

Table-2 NMR (COO,): δ2.602Hd, d, t 24.4Hz 6.8
4.6.84δ6.47 2Hd, t 47
．． 2Hz 6.8465.6-6.0 18 m 66.1-7.0 38 m 67.0-7.5 5t (m In 2910, 1670.1485.1445.740.6
9ON&lR (C mouth α,): δ0.84 611 t 6.48
δ1.0-1.7 1611 m 62.1-2.44Hm δ2.70 2Hd, d, t 23.8.6.
84.6.84δ4,44 28 d,t
46.8.6.84δ6.11 114
t 6.84IR(neat) 2900.2850, 2250.1715.1460.
1380.735 Product PkL3 NMR (C α): 52.06 311 d 1.54 δ2.6
1 211 d, d, t 22.7.6.4
8.6.48δ4.50 2tl d,t 4
7.5,6.48δ5.77 Ill t, q
6.48.1.54δ7.1-7.4 511
m fR(neat) 2950, 1595.1490.1440.755.6
95 Product Nα4 NMR (C mouth α3): 60.77 31 (t 5.76δ1.L-1
,512tl m δ1.60 311 s 61,8-2.0 211 m δ2.34 211 d, d, t 18
, 6.70, 6.68δ4J6 2Hd,t
46.8.6.68δ4.9-5. Llft m IR (mouth eat)

Claims (1)

[Claims] General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・(
I) (In the formula, R_1 is hydrogen, an alkyl group, or a phenyl group, R_2 is a hydrocarbon group, and R_3 is hydrogen or a hydrocarbon group.) Reacting a hydrogen fluoride-amine complex with a cyclopropane derivative represented by General formula (II) characterized by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼
I) A method for producing a 4-fluoro-1-butene derivative represented by (wherein R_1, R_2 and R_3 have the same meanings as above).