JPH07103066B2 - Method for producing α-haloenone form - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention is represented by the general formula (I). (In the formula, X ¹ and X ² represent a chlorine atom, a bromine atom or an iodine atom, and R ¹ is a linear or branched alkyl group having 3 to 10 carbon atoms, or an unsubstituted or at least one carbon atom. C4-C7 cycloalkyl group substituted with C1-C4 alkyl group, or C3-C12 linear or branched alkenyl group, or optionally substituted phenyl group, phenoxy group Or a phenoxyalkyl group, or a linear or branched alkynyl group having 3 to 12 carbon atoms) in the presence of zinc and a dialkylaluminum halide in the general formula (II) R ^2- CHO- (II) (wherein R ² is an optionally substituted 5-membered ring, an optionally substituted bicyclo [3.3.0] octane skeleton or an optionally substituted bicyclo [4.3.0] nonane Represents the skeleton) It is reacted with I to the aldehyde, then substituted sulfonyl chloride or acetic anhydride, and the general formula which comprises treating with a base (IV) [In the formula, A represents X ¹ or X ² (X ¹ and X ² are chlorine atoms,
Represents a bromine atom or an iodine atom. ) R ¹ and R ² have the same meanings as described above. And a method for producing an α-haloenone form represented by

By using the method of the present invention, the following formula (V) The bicyclo [3.3.0] octane derivative represented by can be easily synthesized. The bicyclo [3.3.0] octane derivative represented by the above formula (V) can easily introduce a triple bond at the 13-14 position by reducing the carbonyl group at the 15 position and treating with a base ( JP 61-2052
22). For example, an oxa represented by the following formula (VI)
Carbacyclin Can be synthesized with high efficiency. Oxa-carbacycline is a substance that is drawing attention as a second-generation carbacyclin, and has a longer lifespan in the body than carbacyclins currently in the clinical stage (where the β-position oxygen atom of carboxylic acid replaces methylene) Characterized by extremely long points [H. Vorbrggen, W. Skuballa and B. Radchel, Kyoto Prostaglandin Conference (Kyoto, November 25, 1984), Pro
gram & Abstracts, p36).

[Prior Art] The α-haloenone structure contained in the above formula (V) is conventionally represented by the following general formula (VII). (Wherein R ¹ has the same meaning as described above, X represents bromine and chlorine, and R ³ represents a lower alkyl group.) [W. Skuballa, E] .Sch
illinger, C.-st.Strzebecher and H.Vorbrggen, J.
Med. Chem., 29 , 313 (1986)]. However, the reaction is
Depending on the aldehyde compound used, the yield may be low or the reaction may not proceed at all, and the development of a general and excellent reaction was considered.

[Problems to be solved by the invention]

As a result of intensive studies to solve the above problems, the present inventors have found that the dihalocarbonyl compound represented by the general formula (I) is far superior to the reagent represented by the general formula (VII). The present invention has been completed by the fact that a method for producing an α-haloenone compound having properties is easily found.

[Means for solving problems]

The dihalo-carbonyl compound represented by the general formula (I), which is the starting material of the present invention, can be produced according to any of the reaction formulas described below.

(In the formula, X ¹ , X ² and R ¹ have the same meanings as described above.) (In the formula, X ¹ , X ² and R ¹ have the same meanings as described above. R ⁴
Is a lower alkyl group. ) [Reaction Formula (I) First Step] In this step, the carbanion of methylene halide is condensed with the aldehyde compound represented by the general formula (VII) which is commercially available or can be easily synthesized to prepare the general formula (IX). ) Is for synthesizing an alcohol compound. A strong base is necessary for the preparation of the galvanion of methylene halide, and lithium diisopropylamide, lithium dicyclohexylamide, lithium diethylamide or the like is used. The reaction is preferably carried out in a solvent in the range of -100 ° C to 0 ° C, and an ether solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane or the like can be used.

[Reaction Formula (I) Second Step]

In this step, the alcohol compound represented by the general formula (IX) obtained in the first step is oxidized to synthesize the dihalo-carbonyl compound represented by the general formula (I). As the oxidizing agent, pyridinium chlorochromate and a swerning agent (oxalyl chloride-dimethyl sulfoxide-triethylamine) can be used. Whichever oxidizing agent is used, the reaction is preferably carried out in a solvent, and a halogenated hydrocarbon solvent such as methylene chloride or chloroform can be used. Also, the reaction temperature is -8 ° C to 5 ° C.
Can be selected.

[Reaction Formula (II) First Step]

In this step, the carbanion of methylene halide is condensed with the ester represented by the general formula (X), which is commercially available or can be easily synthesized, to give the general formula (I).
To produce a dihalo-carbonyl compound. The reagents and reaction conditions used in the reaction are exactly the same as those in the above [Reaction formula (I) first step].

The dihalo-carbonyl compound represented by the general formula (I) can be converted into an α-haloenone compound according to the following reaction formula.

(In the formula, X ¹ , X ² , A, R ¹ and R ² have the same meanings as described above, and R ⁵ represents a substituted sulfonyl group or an acetyl group.) [First Step] A dihalo-carbonyl compound represented by the formula (I) is reacted with a dialkylaluminum halide in the presence of zinc powder to form an alumina enolate, which is condensed with an aldehyde derivative represented by the general formula (II) to be represented by the general formula (III). It is for producing an alcohol body. This reaction is carried out in a solvent, and an ether solvent such as tetrahydrofuran, ether or dimethoxyethane is used. As the dialkylaluminum halide used, dimethylaluminum chloride, diethylaluminum chloride and the like are particularly preferable. The reaction proceeds smoothly in the range of -50 ° C to room temperature.

[Second step]

This step is carried out by the general formula (III) obtained in the first step.
The alcoholic body represented by the above formula is converted into the sulfonyloxy body or the acetate body represented by the general formula (XI). This reaction is carried out in a solvent, and a halogenated hydrocarbon solvent such as methylene chloride or chloroform,
Alternatively, a solvent such as pyridine can be used. As the reaction reagent, a substituted sulfonyl chloride such as methanesulfonyl chloride or paratoluenesulfonyl chloride, or acetic anhydride is used. When the reaction is carried out in a halogenated hydrocarbon solvent, the reaction is carried out in the presence of triethylamine as a base. The reaction proceeds smoothly in the range of -78 ° C to -15 ° C.

[Third step]

In this step, the sulfonyloxy derivative represented by the general formula (XI) obtained in the first step is treated at −10 ° C. to room temperature in the presence of triethylamine or pyridine or DBU to obtain the general formula (IV). Α-
It is for producing a haloenone form. The reaction is carried out in a halogenated hydrocarbon solvent such as methylene chloride or chloroform, or a solvent such as pyridine. As will be shown in Examples below, it is easy to carry out the second step and the third step in the same flask by judiciously selecting the reaction conditions.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples.

Reference example 1 1-methyl-3-heptinal (3.
3g, 25.8mmol) and dibromomethane (3.6ml, 51.6mmol)
Was dissolved in THF (50 ml). Lithium dice at -78 ° C
A solution of chlorhexylamide in THF (20 ml, 51.6 mmol) was added dropwise over 30 minutes. After stirring at −78 ° C. for 60 minutes, a saturated ammonium chloride aqueous solution was added at the same temperature. Ether was added to the reaction solution and the insoluble matter was filtered through Celite, and extracted with ether. The ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product of 1,1-dibromo-3-methyl-5-octin-2-ol (5.49 g).
Got

Under an argon atmosphere, 1,1-dibromo-3-methyl-5-
Octin-2-ol (5.49 g, 18.4 mmol) was dissolved in methylene chloride (60 ml), powdered 4A-molecular sieves (5.49 g) and PCC (7.9 g, 36.8 mmol) were added, and the mixture was stirred for 2 days. After adding ether to the reaction solution, the reaction solution was filtered by flow lysyl column chromatography (ether) and washed with ether, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ether: n-hexane = 1: 40), 1,1-dibromo-3-methyl-5-octynyl-2-one (4.52 g, 83%) Got

IR (neat): 3000,2950,1740,1450,1380,1320,1000,700c
m ^-1 NMR (CDCl ₃ ) δ: 6.0 (s, 1H), 2.23 (m, 5H), 1.26 (d, J
= 7.5Hz, 3H), 1.06 (t, J = 12Hz, 3H) Mass (m / z): 215 (M ⁺ −79,7), 136 (26), 124 (75), 12
3 (100) Reference example 2 By the same method as in Reference Example 1, hexanal, (R)-
Corresponding dibromoketone compounds were synthesized from (+)-β-citronellal, cyclohexanecarboxaldehyde, phenoxyacetaldehyde, and 2β-methyl-4-heptynylaldehyde. The yield and IR and NMR spectrum data are shown in Table I below.

Reference example 8 Lithium diisopropylamide ether-THF (40 ml, volume ratio, 3: 1, 20 mmol) at −100 ° C. under argon atmosphere.
Solution of methylene dibromide (3.8g, 22mmol) in THF (20m
l) was added and the mixture was stirred at the same temperature for 15 minutes. Methyl-2-methyl-4-heptinate (1.54g, 10mmol) TH at -100 ° C
The F solution (10 ml) was added dropwise, and the mixture was stirred at -100 to -60 ° C for 2 hours and 30 minutes. A 10% aqueous hydrochloric acid solution was added dropwise to the reaction solution, the ether layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was subjected to silica gel column chromatography (ether: n-hexane =
1:40) to obtain 1,1-dibromo-3-methyl-5-octynyl-2-one (2.51 g, 85%). IR (nea
t): 3000, 2950, 1740, 1450, 1380, 1320, 1000, 700 cm ^-1 NMR (CDCl ₃ ) δ: 6.00 (s, 1H), 2.23 (m, 5H), 1.26 (d, J
= 7.5Hz, 3H), 1.06 (t, 12Hz, 3H) Mass (m / z): 215 (M ⁺ −79,7), 136 (26), 124 (75), 12
3 (100) Reference Examples 9-10 In the same manner as in Reference Example 8, corresponding dibromoketone compounds were synthesized from caproic acid methyl ester and phenoxyacetic acid methyl ester at 76% and 83%, respectively. The spectral data of them were in agreement with those of the compounds obtained in Reference Examples 3 and 6.

Example 1 Zinc dust (17.8 mg, 0.274 mmol) and a catalytic amount of cuprous bromide were suspended in THF (1 ml) under an argon atmosphere. Diethyl aluminum chloride at room temperature (1.44M hexane solution,
0.19 ml, 0.274 mmol) was added and the mixture was stirred at the same temperature for 10 minutes. −
[3E- (4-t-Broxycarbonyl-3-oxa-butylidene) -6-exo-formyl-7-endo-tetrahydropyranyloxy-cis-bicyclo [3.
3.0] Octane] (45 mg, 0.14 mmol) and 1,1-dibromo-3β-methyl-5-octynyl-2-one (170 mg, 0.
A THF solution (2 ml) of 576 mmol) was slowly added dropwise over 15 minutes, and then the mixture was stirred at the same temperature for 60 minutes. A saturated aqueous solution of potassium hydrogen carbonate was added to the reaction solution, which was extracted with ether. The ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated, the obtained residue was dissolved in methylene chloride (2 ml), and triethylamine (0.29 m
(1, 2.1 mmol) was added, methanesulfonyl chloride (0.054 ml, 0.7 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 15 hours. Ice water was added to the reaction solution, and the mixture was extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography (ether: n-hexane =
1: 3) and purified [3E- (4-t-butoxycarbonyl-3-oxa-butylidene) -6-exo- (2-bromo-3-oxo-4β-methyl-trans-1-nonene-6. -Inyl) -7-endo-tetrahydropyranyloxy-cis-bicyclo [3.3.0] octane] (45 mg, 67
%) Was obtained.

IR (neat): 2930, 2850, 1740, 1690, 1200, 820 NMR (CDCl ₃ ) δ: 7.10 (dd, J = 9Hz, 1H), 5.53 (t, J = 12H
z, 1H), 4.66,4.53 (eachbs, totallH), 4.10 (d, J = 7.5H
z, 2H), 3.96 (s, 2H), 1.16 (d, J = 7Hz, 2H), 1.06 (t, J
= 7.5Hz, 3H) Mass (m / z): 379 (5), 378 (11), 376 (11), 105 (2
6), 85 (100), 79 (12), 67 (42), 57 (95), 55 (31),
43 (37), 41 (67), 29 (30) Example 2 Under an argon atmosphere, zinc dust (19.6 mg, 0.3 mmol) and a catalytic amount of cuprous bromide were suspended in THF (1 ml). Diethyl aluminum chloride (1.15M hexane solution, 0.
(26 ml, 0.3 mmol) was added and the mixture was stirred at the same temperature for 10 minutes. -5 ° C
At [3E- (2-methoxy-ethylidene) -6-exo-formyl-7-endo-tetrahydropyranyloxy-cis-bicyclo [3.3.0] octane] (74 mg, 0.252 mmo
l) and 1,1-dibromo-2-heptanone (171mg, 0.63mm
ol) in THF (2 ml) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 40 minutes. A saturated aqueous solution of potassium hydrogen carbonate was added to the reaction solution, followed by extraction with ether. The ether layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was dissolved in methylene chloride (2 ml). Triethylamine (0.57ml, 4.16mmol) at -20 ℃
After the addition of methanesulfonyl chloride (0.108 ml, 1.
(37 mmol) was added dropwise and the mixture was stirred at 0 ° C. for 2 hours. Ice water was added to the reaction solution, which was extracted with ether. The ether layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ether: n-hexane = 1: 4) [3E
-(Methoxy-ethylidene) -6-exo- (2-bromo-3-oxo-trans-1-octenyl) -7-endo-tetrahydropyranyloxy-cis-bicyclo [3.3.0] octane] (92 mg, 75 %) Was obtained.

NMR (CDCl ₃ ) δ: 7.06 (dd, J = 9Hz, 1H), 5.50 (t, J = 12H
z, 1H), 4.66,4.53 (eachbs, total, lH), 3.90 (d, J = 7H
z, 2H), 3.30 (s, 3H), 0.86 (t, J = 9Hz, 3H) Examples 3 to 6 In the same manner as in Example 2, [3E- (2-methoxy-ethylidene) -6-exo-formyl-7-endo-tetrahydropyranyloxy-cis-bicyclo [3.3.0] octane] and dibromoketone compound were prepared. The following compounds were synthesized by the reaction. The yield and NMR data are shown in Table 2.

Example 7 Under an argon atmosphere, zinc dust (11.0 mg, 0.17 mmol) and a catalytic amount of cuprous bromide were suspended in THF (1 ml). Diethyl aluminum chloride (1.15M hexane solution,
0.134 ml, 0.14 mmol) was added dropwise and the mixture was stirred at the same temperature for 10 minutes.
[3- (4-t-methoxycarbonyl-1-butenyl) -7-exo-formyl-8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] ( A THF solution (1.5 ml) of 50 mg, 0.14 mmol) and 3,3-dibromo-cyclohexane-2-one (100 mg, 0.35 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of potassium hydrogen carbonate was added to the reaction solution, which was extracted with ether. The ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated, the obtained residue was dissolved in methylene chloride (1 ml), triethylamine (0.207 ml, 1.5 mmol) was added at -20 ° C, and then methanesulfonyl chloride (0.039 ml, 0.5 mmol) was added dropwise. Then, the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, and the mixture was extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ether: n-hexane = 1: 2) [3- (4-methoxycarbonyl-1-butenyl) -7-exo- (2-bromo-3-
Oxo-4-cyclohexane-trans-1-propenyl) -8-endo-tetrahydropyranyloxy-cis-bicyclo [4.3.0] non-2-ene] (55 mg, 71%) was obtained.

IR (neat): 2940,2860,1730,1680,1200,810cm ^-1 NMR (CDCl ₃ ) δ: 7.01 (dd, J = 1.5,9Hz, 1 / 2H), 6.86 (d
d, J = 3,12Hz, 1 / 2H), 6.13 (d, J = 16Hz, 1 / 3H), 5.85 (d,
J = 12Hz, 2 / 3H), 5.60 (bs, 1H), 5.30 (m, 1H), 4.60 (m,
1H), 3.70 (s, 3H) Mass (m / z): 463 (M ⁺ −85, trace), 314 (11), 244 (2
8), 85 (100).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 49/813 69/738 Z 9279-4H C07D 309/12

Claims (1)

[Claims] 1. A general formula (In the formula, X ¹ and X ² represent a chlorine atom, a bromine atom or an iodine atom, and R ¹ is a linear or branched alkyl group having 3 to 10 carbon atoms, or an unsubstituted or at least one carbon atom. C4-C7 cycloalkyl group substituted with C1-C4 alkyl group, or C3-C12 linear or branched alkenyl group, or optionally substituted phenyl group, phenoxy group Or a phenoxyalkyl group, or a linear or branched alkynyl group having 3 to 12 carbon atoms) in the presence of zinc and a dialkylaluminum halide, represented by the general formula R ² -CHO (formula In the formula, R ² represents an optionally substituted 5-membered ring, an optionally substituted bicyclo [3.3.0] octane skeleton or an optionally substituted bicyclo [4.3.0] nonane skeleton.)
A general formula characterized by reacting with an aldehyde derivative represented by and then treating with a substituted sulfonyl chloride or acetic anhydride and a base. [In the formula, A represents X ¹ or X ² (X ¹ and X ² are chlorine atoms,
It is a bromine atom or an iodine atom. ), R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the (alpha)-halo enone body represented by these.