JP2536026B2 - Process for producing α, β-substituted cyclopentanone derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a medicinal and agrochemical or an intermediate thereof, particularly, an α, β-substituted cyclopenta useful as a prostaglandin or an intermediate thereof known to have strong physiological activity. The present invention relates to a method for producing a non-derivative.

2. Description of the Related Art Problems to be Solved by Conventional Techniques and Inventions α, β-Substituted cyclopentanone derivatives have hitherto attracted attention as pharmaceuticals, agricultural chemicals or intermediates thereof, particularly prostaglandins (PG) and synthetic intermediates thereof. .

For example, as prostaglandins and synthetic intermediates thereof, the following general formula [G] Are known.

PGE ₁ : R = (CH ₂ ) ₆ CO ₂ H, Z = Y = H, PGE ₂ : Z = Y = H, Intermediate _{(A): R = CH 2} CH = CH 2, Z = Y = Si t BuMe 2 prostaglandins of PGE _1, PGE ₂ has been used in practice as a pharmaceutical, Further, the intermediate (A) is important as a synthetic intermediate for various prostaglandins [Kurozumi et al., Chemical Pharmaceutical Burtin (Che
m, Pharm, Bull.), 35 , 1102 (1982)].

Conventionally, as one of the reactions for producing such prostaglandins, a prostaglandin E type can be synthesized from a α-cyclopentenone derivative having no substituent at the β-position by a so-called two-component coupling reaction represented by the following formula. Is known [MJWeiss et al., Journal Organic Chemistry.
emistry) 44 , 1439, (1979)].

However, the above reaction has a very low yield of only 12%.

Therefore, various nucleophiles have been proposed for this type of reaction. For example, the nucleophilic reagent used in the above formula Instead of, [K.G.Unchi et al., Journal American Chemical Society (KG Untch, J.Am.Chem.So.
c.), 94 , 7828 (1972)], Method [R. Pappo, PWCollins, Tetrah (R. Pappo, PWCollins, Tetrah
edron Lett.), 4217 (1975)], A method using a [Kurozumi et al., Chemical Pharmaceutical Suchika Le Burqin (Chem.Pharm.Bull.), 35, 1102 (1982) ] and A method of using the [Sea J. Sea, Journal American Chemical Sosaiyati (CJSih, J.Am.Chem.Soc.), 97 , 8
65 (1975)].

However, in all of these methods, the yield of prostaglandins was low, the maximum was about 50-60% at most, and the yield was usually lower than that.

Since the starting materials used in this type of reaction are very expensive, the low yield in this reaction step is a major problem in the binary reaction. Furthermore, in the methods of (1) and (4), since the alkyl chain in the nucleophile is effective only at 1/2, the expensive alkyl chain portion is utilized only at the maximum of 1/2 × (yield). In addition, the methods (3) and (4), which have relatively high yields among these methods, use phosphine and thiol, and therefore, they are very toxic and their products are very difficult to separate. There was a problem that it took time.

The present invention has been made with the object of overcoming the above problems and completing a two-component coupling reaction method for producing a prostaglandin or a synthetic intermediate thereof at a high yield and at a low cost.

Means for Solving the Problems As a result of intensive studies for achieving the above-mentioned object, the present inventors have found that the general formula [I] Lithium 2-thienylcyanocopper (I) complex as a nucleophilic reagent for the α-substituted cyclopentenone derivative represented by [BHLipshutz, Tetrahedron Lett.] 28 , 945 (19
87)] and an organolithium reagent, that is, the general formula [II] When the nucleophilic reagent represented by the formula (3) is used, the so-called two-component coupling reaction proceeds smoothly, and the general formula [III] It was found that the target α, β-substituted cyclopentanone derivative represented by

In this case, it is known that this mixed complex undergoes a conjugated addition reaction with enone, but even if a conventional nucleophilic reagent undergoes a conjugated addition reaction with enone, when it is applied to a two-component reaction, a normal reaction is almost impossible. It does not proceed, and the yield is 0.
Although only a few examples of synthesizing prostaglandins with low yields are found in the above-mentioned documents, the present invention aimed at prostaglandins or synthetic intermediates thereof using this mixed complex. When the two-component ligation reaction of the invention is carried out,
It is an unexpected new finding of the present inventors that the target substance can be obtained in a high yield.

Therefore, the present invention provides a compound represented by the general formula [I] (However, W in the formula is (α-OZ, β-H) or (α-H, β-O)
Z) and Z each represent a hydroxyl-protecting group. R ¹ has ¹ carbon atom
To 15 substituted or unsubstituted alkyl groups, alkenyl groups, and alkynyl groups. ) And an α-substituted cyclopentenone derivative represented by the general formula [II] (However, in the formula, R ² is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted phenyl group, Y is a hydroxyl-protecting group, Represents a single bond, a double bond or a triple bond. ) A general formula [III] characterized by reacting with a nucleophilic agent represented by (However, in the formula, W has the same meaning as described above, but W is (α-
When OZ, β-H), X is (α-H, And when W is (α-H, β-OZ), X is Is. Z, R ¹ , R ² and Has the same meaning as above. The manufacturing method of the (alpha), (beta)-substituted cyclopentanone derivative represented by these is provided.

 Hereinafter, the present invention will be described in more detail.

In the method for producing an α, β-substituted cyclopentanone derivative of the present invention, the first starting material represented by the general formula [I] The α-substituted cyclopentenone derivative represented by is a known compound and can be produced by various methods. For example, Japanese Patent Application Sho
General formula [A] as described in No. 62-194947 (However, W in the formula is (α-OZ, β-H) or (α-H, β-O)
Z) and U are (α-OZ ′, β-H) or (α-H, β-O)
Z ′). Z and Z ′ each represent a hydroxyl-protecting group, but Z and Z ′ may be the same or different from each other. To the substituted cyclopentanone derivative represented by the formula [B] R ¹ M [B] (wherein R ¹ is a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, an alkenyl group, an alkynyl group, M is Li, Na,
A metal selected from K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al and Sn or a group containing the metal is shown. ) Is reacted with a nucleophilic reagent represented by the general formula [I] (Wherein W and R ¹ have the same meanings as described above), and a method for producing an α-substituted cyclopentenone derivative can be mentioned.

Here, in the general formula [I], R ¹ and W are as described above, and R ¹ is a methyl group, an ethyl group, an n-octyl group, a 7-methoxycarbonyl-heptyl group, a 7-
Substituted or unsubstituted alkyl group such as (1-ethoxyethyl) heptyl group, allyl group, (Z) -7- (tetrahydropyranyl-2-oxy) carbonyl-2-heptenyl group, (Z) -7-methoxy Carbonyl-2-heptenyl group, (E) -7-methoxycarbonyl-5-heptenyl group, 7-methoxycarbonyl-2,3-heptadienyl group, (Z, E) -7-methoxycarbonyl-2,5-heptadienyl group And substituted or unsubstituted alkenyl groups, propargyl groups, substituted or unsubstituted alkynyl groups such as 7-methoxycarbonyl-2-heptynyl group, and the like. Further, a protective group Z for the hydroxyl group in the OZ group that defines W
Are a trialkylsilyl group such as a trimethylsilyl group or a t-butyldimethylsilyl group; an alkoxyalkyl group such as a methoxymethyl group or an ethoxyethyl group;
Examples thereof include an aralkyloxyalkyl group such as a benzylmethyloxymethyl group; a trityl group; and a tetrahydropyranyl group.

The general formula [II] which is the second starting material of the present invention The nucleophilic reagent represented by can be produced by a usual method, for example, a method of mixing commercially available 2-thienylcyanocopperlithium with a predetermined organolithium reagent, or the like.

In the above general formula [II], R ² and Y are as described above, and specific examples of R ² include a methyl group, an ethyl group, and n.
-Propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, amyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, 2-methylhexyl group, 2- Methyl-2-hexyl group, 2-hexyl group, cyclopentyl group, cyclohexyl group, cyclohexylmethyl group, hexa-4-in-2-yl group, hepta-4-in-2-yl group, 2,6-dimethyl- Hepta-5
-En-1-yl group, penta-1-en-1-yl group,
Penta-2-en-1-yl group, hexa-1-en-2
-Yl group, 3-ethoxy-2-methyl-propane-2-
Group, ethoxyethyl group, 5-methoxyhexyl group,
6-methoxy-2-hexyl group, halogenated methyl group,
Halogenated n-butyl group, halogenated n-pentyl group,
Nonyl halide group, phenyl group, benzyl group, halogenated phenyl group, n-pentyloxymethyl group, 1-ethoxy-2-methyl-propan-2-yl group, phenoxymethyl group, benzyloxymethyl group, p-chloro. Phenoxymethyl group, 2-phenylethyl group, benzyloxyethyl group, p-fluorophenoxymethyl group, phenylacetylenyl group, m-chlorophenoxymethyl group, m-trifluoromethyl-phenoxymethyl group, 1-butyl-
Examples thereof include a cyclopropyl group, a 3-ethyl-cyclopentyl group, a benzothiophen-5-yl group, a 2-octenyl group and the like.

In addition, Y is a hydroxyl-protecting group, and the same groups as the above-mentioned protecting group Z can be exemplified. In this case, the protecting groups Z and Y may be the same or different.

The present invention comprises reacting an α-substituted cyclopentenone derivative represented by the general formula [I] with a nucleophilic reagent represented by the general formula [II],
An α, β-substituted cyclopentanone derivative represented by the general formula [III] is obtained. In this case, the general formula [I
The amount of the nucleophilic reagent of I] is usually 0.5 to 4 equivalents, particularly 0.8 to 1.8 equivalents to the α-substituted cyclopentenone derivative of the general formula [I].
It is preferable to use an equivalent amount.

A solvent may be used in the reaction, but the solvent used in the reaction may be any one that does not inhibit the reaction, and examples thereof include tetrahydrofuran, hexane, pentane and diethyl ether.

The reaction temperature is usually −100 to 50 ° C., preferably −80.
~ 0 ° C, and the reaction time is usually 5 minutes to 50 hours.

Effects of the Invention According to the present invention, an α, β-substituted cyclopentanone derivative useful as a drug, an agricultural chemical or an intermediate thereof, particularly a prostaglandin or a synthetic intermediate thereof can be obtained in a higher yield than ever before. it can. Moreover, it is superior to the conventional method in that all the alkyl chains in the nucleophilic reagent are effective and that the thiophene is volatile and thus can be easily separated from the product. Therefore, drug substances such as prostaglandin E ₁ and prostaglandin E ₂ can be manufactured at low cost by way of such an α, β-substituted cyclopentanone derivative.

Hereinafter, the present invention will be specifically described with reference to examples.
The present invention is not limited to the examples below. In addition,
In the following formulae, Me represents a methyl group and ^t Bu represents a tert-butyl group.

[Example 1] Under an argon atmosphere, 2 ml of a diethyl ether solution containing 276 mg (0.75 mmol) of compound (1) was stirred, and the temperature was -78 ° C.
^T BuLi 0.88 ml (1.5 mmol, concentration 1.70 in pentane)
M) was added and stirred at this temperature for 1 hour. Next, 2 ml of tetrahydrofuran was added, then 2.21 ml of lithium 2-thienyl cyanocouprate (0.75 mmol, concentration 0.34 M in tetrahydrofuran) was added, and the mixture was stirred at -78 ° C for 20 minutes. Further, 3 ml of a tetrahydrofuran solution containing 176 mg (0.50 mmol) of the compound (2) was added dropwise at -78 ° C, and the temperature was raised to room temperature for 1 hour. After the reaction, 10 ml of a saturated aqueous solution of ammonium chloride and 10 ml of hexane were added, and the mixture was stirred at room temperature for 1 hour. After separating the organic layer, the aqueous layer was further extracted with 10 ml of hexane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel column chromatography to obtain 268 mg (yield 90%) of compound (3). The analytical value of the compound (3) is shown. ¹ H NMR (CDCl ₃ , CHCl ₃ ) δ 0.13 (s, 12H), 0.91 and 0.93 (2
s, 18H), 0.79-1.04 (m, 3H), 1.15-2.79 (m, 20H), 3.
64 (s, 3H), 3.91-4.21 (m, 2H), 5.13-5.74 (m, 4H). ¹³ C NMR (CDCl ₃ ) δ 215.0,173.8,136.5,130.7,128.8,126.
9,73.4,72.7,54.0,52.8,51.4,47.8,38.6,33.6,31.9,26.
8,26.0,25.8,25.5,25.1,24.8,22.7,18.3,18.1,14.0,-
4.2, −4.5. IR (neat): 2930,1740,1465,1365,1250,840,780 (c
m ^-1 ). ▲ [α] ¹⁹ _D ▼ -49.3 ° (C = 1.14, CH ₃ OH) The value of ▲ [α] ¹⁹ _D ▼ described in the literature is -49.
9 ° (C = 1.02, CH ₃ OH) [Noyori et al., Journal American Chemical Society (J. Am. Chem. Soc.), 10
7 , 3348 (1985)].

[Example 2] Under an argon atmosphere, the compound (1) 350mg (0.952 mmol) ^t at -78 ° C. in diethyl ether solution 2ml containing BuLi1.
12 ml (1.91 mmol, concentration 1.70 M in pentane) were added and stirred at this temperature for 1 hour. Next, 2 ml of tetrahydrofuran was added, and then 2.80 ml of lithium 2-thienylcyanocouprate (0.952 mmol, concentration 0.34M in tetrahydrofuran) was added, and the mixture was stirred at -78 ° C for 20 minutes. Further, 3 ml of a tetrahydrofuran solution containing 160 mg (0.63 mmol) of the compound (4) was added dropwise at -78 ° C, and the mixture was stirred for 20 minutes. Next, the temperature was raised to room temperature over 1 hour, 10 ml of a saturated ammonium chloride aqueous solution and 10 ml of hexane were added, and the mixture was stirred for 1 hour. After separating the organic layer, the aqueous layer was further extracted with 10 ml of hexane. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel column chromatography to obtain 306 mg (yield 98%) of compound (5). The analytical value of the compound (5) is shown. ¹ H NMR (CCl ₄ , PhH) δ 0.06, 0.09 and 0.13 (3s, 12H), 1.0
4 and 1.06 (2s, 18H), 0.82-1.13 (m, 3H), 1.13-2.73
(M, 14H), 3.87-4.24 (m, 2H), 4.79-5.23 (m, 2H),
5.25-6.00 (m, 3H). ¹³ C NMR (CDCl ₃ ) δ214.7,136.5,135.2,128.6,117.1,73.
4,72.8,53.5,52.4,47.6,38.6,31.9,25.9,25.8,25.0,22.
6,18.2,18.0,14.0−4.2, −4.7. IR (neat): 2940,1745,1465,1365,1255,1115,840 (c
m ^-1 ). ▲ [α] ²⁰ _D ▼ -66.2 ° (C = 0.90, CHCl ₃ ). Rf value 0.58 (SiO ₂ TLC; hexane: ethyl ether = 5: 1) [Example 3] In an argon atmosphere, 40 ml of a diethyl ether solution containing 8.09 g (22 mmol) of compound (6) [racemic compound (1)] was charged with 25.9 ml of ^t BuLi (44 mmol, concentration of 1.70 M in pentane) at -78 ° C. In addition, the mixture was stirred at this temperature for 1 hour. Next, after adding 40 ml of tetrahydrofuran, 64.7 ml of lithium 2-thienyl cyanocuprate (22 mmol, concentration 0.34M in tetrahydrofuran) was added, and -78
Stirred for 20 minutes at ° C. Further, 40 ml of a tetrahydrofuran solution containing 5.04 g (20 mmol) of compound (7) [racemic compound (4)] was added dropwise at −78 ° C., and the mixture was stirred for 20 minutes. Next, the temperature was raised to room temperature over 1 hour, 150 ml of saturated ammonium chloride aqueous solution and 100 ml of hexane were added, and the mixture was stirred for 1 hour. After separating the organic layer, the aqueous layer was further extracted with 100 ml of hexane. The organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography to give compound (8) [racemic compound (5)] 9.80 g (yield 99%).
I got The analytical value of the compound (8) was the same as that of the compound (5).

[Example 4] Under an argon atmosphere, 552 mg (1.5 mmol) of compound (1) was dissolved in 4 ml of n-hexane, and 0.86 ml of n-BuLi at -78 ° C.
(1.4 mmol, concentration 1.63M in n-hexane) was added and stirred at this temperature for 1 hour.

Next, 7.2 ml of lithium 2-thienyl cyanocuprate
(1.8 mmol, concentration 0.25 M in tetrahydrofuran) was added, and the mixture was stirred at -78 ° C for 30 minutes.

Further, 3 ml of a tetrahydrofuran solution containing 380 mg (1.0 mmol) of the compound (9) was added dropwise at -78 ° C, and the mixture was stirred at -78 ° C for 30 minutes and then heated to 0 ° C in 2.5 hours. 20% after reaction
The reaction solution was added dropwise to 15 ml of an aqueous ammonium chloride solution and 15 ml of n-hexane.

After separating the organic layer, the aqueous layer was further extracted twice with 15 ml of n-hexane.

The organic layer was dried over 2 g of magnesium sulfate, concentrated and then subjected to silica gel chromatography [silica gel 24.5 g (Merck 773
4), purified with n-hexane / ethyl acetate = 20/1),
317 mg (yield 51%) of compound (10) was obtained. Compound (10)
The analysis value of is shown. ¹ H NMR (CDCl ₃ ) δ 0.00-0.04 (m, 12H), 0.83-0.09 (m, 2
1H), 1.25-1.65 (m, 16H), 1.90-1.92 (dt, 1H), 2.12-2.
18 (dd, 2H), 2.28-2.31 (t, 3H), 2.41-2.43 (dt, 1H),
2.58-2.62 (ddd, 1H), 4.02-4.09 (m, 2H), 4.52-4.56 (d
d, 2H), 5.20-5.31 (ddd, 2H) .5.50-5.59 (m, 2H), 5.87-
5.92 (m, 1H)

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07C 405/00 504 7419-4H C07C 405/00 504T C07D 309/12 C07D 309/12 C07F 7/18 C07F 7 / 18 A

Claims (1)

(57) [Claims] 1. A general formula [I] (However, W in the formula is (α-OZ, β-H) or (α-H, β-O)
Z) and Z each represent a hydroxyl-protecting group. R ¹ has ¹ carbon atom
To 15 substituted or unsubstituted alkyl groups, alkenyl groups, and alkynyl groups. ) And an α-substituted cyclopentenone derivative represented by the general formula [II] (Wherein, R ² is a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted phenyl group, Y is a hydroxyl-protecting group, Represents a single bond, a double bond or a triple bond. ) A general formula [III] characterized by reacting with a nucleophilic agent represented by (However, in the formula, W has the same meaning as described above, but W is (α-
When OZ, β-H), X is (α-H, And when W is (α-H, β-OZ), X is Is. Z, R ¹ , R ² and Has the same meaning as above. The manufacturing method of the (alpha), (beta)-substituted cyclopentanone derivative represented by these.