JPH0210151B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to prostaglandin D ₁ (hereinafter referred to as PGD ₁
(abbreviated as )). More specifically, the present invention relates to a novel production method for inducing PGD type ₁ in which the 9th and 15th positions are protected with a group that forms an acetal bond with the oxygen atom of a hydroxyl group, and the 11th position is protected with a silyl group. PGD ₁ is a primary PG group that includes PGE ₁ and PGF ₁ α.
It belongs to the type 1 PG group together with PGE, and is a compound with a strong and unique biological activity, second only to PGE in terms of white platelet aggregation inhibiting activity, but its more detailed biological activity is not well known. Recently, a compound with antiplatelet and antiasthmatic effects was discovered in PGD ₁ analogues (Erick, William, Corinthau, JP-A-Sho).
57-102877). Conventionally, there are four methods for producing PGD type ₁ .
Namely, (1) a method of obtaining biosynthesis from all-cis-8,11,14-eicosatrienoic acid (CJ.SihS,
Biochemistry, 11, 2271 (1972)). (2) A method of obtaining PGF ₁ α by selective participation of hydroxyl groups at positions 9 and 11. (G, L, BundyS, J,
(See Med, Chem, 26, 790 (1983)). (3) Method of obtaining from a compound in which the carbonyl group at position 11 is protected with a 1,3-dithioacetal group (A,
T, Hewson S, Fitnahedwn hitt., 23, 561
(1982)). (4) Protected with different silyl groups at positions 9, 11, and 15
Method of deriving from PGF ₁ α derivative (JT.W.Hart
S., J.Chem.Comm, 156 (1979)) is known. However, in these methods (1), not only is it difficult to obtain the raw material polyunsaturated fatty acids, but biosynthesis always requires
PGE ₁ and PGF ₁ α are produced as by-products, and these must be separated in order to produce PGD ₁ , which is difficult from an industrial standpoint. In the chemical synthesis method (2), the reaction must be delicately controlled to selectively oxidize only the 11th position of the two free hydroxyl groups at the 9th and 11th positions, and the yield is low. This is not necessarily industrially satisfactory. In method (3), the carbonyl at position 11 is 1,3-
Since a dithioacetal-protected intermediate is used, the steric structure at position 12 cannot be controlled during the synthesis of the PG skeleton, and the product is a mixture of non-natural isomers, making it difficult to separate them. In method (4), positions 9 and 11 are protected with the same protecting group different from the silyl protecting group at position 15, and only position 11 is selectively protected with the same protecting group different from the 9-position. death,
This method selectively deprotects only position 11, distinguishing it from position 9, and requires delicate reaction control.
Furthermore, the process is complicated in that the protecting group at position 11 is converted twice, and this method cannot be said to be industrially satisfactory. The present inventors focused on this point, and as a result of intensive research to find an advantageous chemical synthesis method for prostaglandin D ₁ , they cleverly utilized the hydroxyl protecting group used in the synthesis of the PG skeleton. Protected with a group that forms an acetal bond with the oxygen atom of the hydroxyl group From the PGF ₁ α series, in which the 6th and 11th positions are protected with a silyl group, only the 11th position is converted to a specified functional group.
The present invention was achieved by successfully obtaining PGD type ₁ . In other words, the following formula (1) In the formula, R ¹¹ represents a C ₁ to _{C 10} alkyl group or a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, and R ² and R ³ are the same or different and are hydrogen atoms, substituted or unsubstituted C ₁ ~ _C10 alkyl group or substituted or unsubstituted 5- to 6-membered cycloalkyl group, ^R31
represents a tri(C ₁ to _{C 7} ) hydrocarbon silyl group,
R ⁴¹ represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group. The hydroxyl group at the 9-position of the prostaglantein F ₁ α group represented by is protected with a group that forms an acetal bond with the oxygen atom of the hydroxyl group, and the following formula (2) is obtained. In the formula, R ¹¹ , R ² , R ³ , R ⁴¹ are the same as above, and R ⁵¹ is
Represents a group that forms an acelyl bond with the oxygen atom of a hydroxyl group, which may be the same as or different from R ⁴¹ . Prostaglantein F ₁ α expressed as
The following formula (3) is characterized in that it is selectively deprotected, then oxidized, and then subjected to deprotection and/or hydrolysis reaction as necessary. In the formula, R ² and R ³ are the same as defined above, R ¹ is a hydrogen atom,
It represents a C ₁ -C ₁₀ alkyl group or a tri(C ₁ -C ₇ )hydrocarbon silyl group, and R ⁴ and ⁵ are the same or different and represent a group that forms an acetase bond with a hydrogen atom or an oxygen atom of a hydroxyl group. This is a method for producing prostaglandin D type ₁ , which is expressed by The prostaglandin D ₁ α group represented by the above formula (1) used in the method of the present invention can be prepared by the previously proposed method (see Japanese Patent Application No. 57-163082). 99462
It can be prepared easily and in high yield from (see No.). In the above formula (1), R ¹¹ represents a C ₁ to C ₁₀ alkyl group or a tri(C ₁ to C ₇ ) hydrocarbon-silyl group. Examples of C ₁ to ^{C 10} alkyl groups include methyl, ethyl, n-pumepyl, iso-propyl,
n-butyl, sec-butyl, tert-butyl, n-
Straight or branched ones such as pentyl, n-hexyl, n-heptyl, n-otatyl, n-nonyl, and n-decyl can be mentioned. Among these, methyl group and ethyl group are preferred. Bird ( _C1 - _C7 )
Examples of hydrocarbon-silyl groups include tri(C ₁ -C ₄ )alkylsilyl groups such as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl; diphenyl (C ₁ -C ₄ ) such as t-butyldiphenylsilyl; ) an alkylsilyl group, a tribenzylsilyl group, etc. R ² and R ³ are the same or different, and examples of the hydrogen atom or substituted or unsubstituted C ₁ to C ₁₀ alkyl group include methyl, ethyl n-propyl,
Iso-propyl, n-butyl, m-pentyl, n
-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl, n-heptyl, n-octyl, and other straight or branched ones. Examples of the unsubstituted 5- to 6-membered cycloalkyl group include a cyclopentyl group and a cyclohexyl group. Examples of substituents for such unsubstituted C ₁ -C ₁₀ alkyl groups and unsubstituted 5- to 6-membered cycloalkyl groups include methyl, ethyl, phenoxy, trifluoromethyl, and trifluoromethylphenoxy groups. Preferably. Especially as R ² ,
Methyl, methyl optionally substituted with a phenoxy group or a trifluoromethylphenoxy group,
n-pentyl, n-hexyl, 2-methyl-1-
Hexyl, cyclopentyl or cyclohexyl groups are preferred, and n-pentyl, n-hexyl, 2-methyl-1-hexyl, cyclopentyl and cyclohexyl are especially preferred. R ³ is preferably a hydrogen atom or a methyl group, particularly preferably a hydrogen atom. R ³¹ represents a tri(C ₁ -C ₇ ) hydrocarbon-silyl group, of which t-butyldimethylsilyl group and triethylsilyl group are preferred. R ⁴¹ is a group that forms an acetal bond with the oxygen atom of a hydroxyl group, such as methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2-ethoxy-2propyl, (2-methoxyethoxyethoxy)
Methyl, benzyloxymethyl, 2-tetrahydropyranylne 2-tetrahydrofuranyl, 6,6
-dimethyl-3-oxa-2-oxo-bicyclo(3,1,0)hex-4-yl group and the like. R ⁴¹ is, among others, a hydrobilanyl group, 1-
Ethoxyethyl group and 2-methoxy-2-propyl group are preferred. Represented by the above formulas (1) to (3) in the method of the present invention
PG class is 8th, 9th, 11th, 12th, 15th,
Since it has an asymmetric carbon atom, various stereoisomers exist, and the PGs in the method of the present invention include these mirror images, optical isomers, and mixtures thereof. The method of the present invention uses prostaclandin of the above formula (1).
The process starts by protecting the hydroxyl group at the 9-position of the D ₁ α group with a group that forms an acetal bond with the oxygen atom of the hydroxyl group. As the protective agent, 2-3-dihydropyran, ethyl vinyl I-ral, acetone dimethyl acetal, etc. are used. These protective agents are used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to prostaglandin D ₁ α as the raw material. As a reaction aid, pyridine para-toluene sulfonate (PPTS), camphorsulfonic acid, etc. are preferably used in an amount of 0.1 to 100% by weight, preferably 1 to 30% by weight, based on the raw material prostaglandin F ₁ α. The reaction can also be carried out in anhydrous ethers, such as ethyl ether, tetrahydromefuran, diotisane, etc., or in anhydrous halogenated hydrocarbons, such as methylene cyclolide chloroform, dichloroethane, etc. The reaction temperature is -10℃~60℃, preferably 0℃~30℃
The reaction proceeds at ℃, and the end point of the reaction is confirmed by observing the disappearance of the raw materials using thin layer chromatography, etc. The reaction solution is thus post-treated by a conventional method, and the product is protected with the 11th-position gacylyl group represented by the above formula (2), and the 9th- and 15th-positions are protected with groups that form an acetal bond with the oxygen atom of the hydroxyl group. PGF ₁ α species are obtained. Next, the silyl protecting group at position 11 of this compound is selectively deprotected. This is achieved in a customary manner by using tetra-n-butylammonium fluoride, hydrogen fluoride-pyridine, particularly preferably tetra-n-butylammonium fluoride. Thus, the following formula (4) (In the formula, R ¹¹ , R ² , R ³ , R ⁴¹ , and R ⁵¹ are the same as above.)
PGF ₁ α species with protected positions 9 and 15 can be easily prepared. This product can be prepared by methods known per se (E, E, Nihiqawa S P
tostaglandio 9, 109 (1975)), oxidize the hydroxyl group at position 11 with a chromic acid-based oxidizing agent such as Jones sample collection, pyridium chlorochromate,
The protecting groups for R ⁴¹ and ⁵¹ may be removed if necessary.
Removal is accomplished, for example, by treating the product in an acetic acid-water-tetrohydrofuran mixture (3:1:1 to 3:2:2) at room temperature (EJCorey et al., J. Amer, Chom.Soc., 24,
6190 (1972)). In addition, if necessary, the 1-position ester group (R ¹¹ )
may be hydrolyzed. Such hydrolysis can be carried out using, for example, an alkaline aqueous solution for F-type PG, and a hydrolase such as lipase or esterase for E-type PG. Thus, the desired expression (3) is expressed by the above equation (3).
PGD type ₁ can be easily obtained in high yield. The characteristics of the method of the present invention are as follows. That is, by directly utilizing the difference in the protection state of the hydroxyl groups at the 9-, 11-, and 15-positions that occurred in the starting material (1), the above formula (4) can be obtained without converting the protecting groups as in conventional methods. This method involves deriving the indicated intermediate and converting it into PGD ₁ class. This method is much more advantageous than conventional methods and can provide PGD ₁ without separating the steric isomers. The method of the present invention will be explained in more detail below with reference to Examples. Reference example 3 1 (103 mg) into a 10 ml eggplant flask and add 1 ml of
Dry _{CH2Cl2 was} added. Cool in a water bath, 33 mg 2,
Add 3 dihydrobirane followed by 14 mg PPTS
was added and stirred at 0°C for 10 minutes and at 30°C for 5 hours.
After diluting the reaction solution with 5 ml of methylene chloride, saturated sodium chloride was extracted. (2 x 10ml) Combine the organic layers,
It was dried with anhydrous sodium sulfate. After concentration under reduced pressure, it was subjected to silica gel column chromatography.
(12 g of silica gel manufactured by Merck; ethyl acetate: hexane = 1:10), 111 mg of 2 as a product (yield 94%)
Obtained. IR (CHCl ₃ ): 1730 cm ^-1 HNMR (CDCl ₃ , 90 MHz, ppm) δ: 0.007 (s, 6, SiCH ₃ ×2), 0.7−1.0 (12, SiC
(CH ₃ ) ₃ andCH ₃ ), 1.1―2.5 (m, 36, CH ₂ ×
17), 4.5-4.8 (m, 2, OCHO x 2), 5.40 (m,
2, vinyl1) TLC: Rf: 0.54 (EtOAc−hexane = 1:4) Optical rotation: [α] = 15.9° (C0.365, MeOH) Reference example 4 3 (26 mg) was placed in a 5 ml test tube, and 0.1 ml of dry CH ₂ Cl ₂ was added. Cool in a water bath, 4.7 mg of 2,
Add 3-dihydrobilane, followed by PPTS0.2
mg at room temperature (20°C) for 10 minutes at 0°C.
After stirring at 30℃ for 1 hour, 2,3-dihydrobilane
0.2 mg of 4.7 mg PPTS was added and stirred at 30°C for 2 hours.
In addition, 2,3-dihydrobirane 4.7 mg, PPTS 0.2
mg was added and stirred for 1 hour. After diluting the reaction solution with 5 ml of methylene chloride, 10 ml of saturated saline was added.
Shake well. After separating the organic layer and the aqueous layer, they were dried over sodium. After concentration under reduced pressure, it was subjected to silica gel column chromatography (1.7 g of Merck silica gel; ethyl acetate:hexane = 1:10) to obtain product 4.
29 mg (yield 97%) was obtained. The spectral data were the same as Reference Example 3. Reference example 5 Add 103.5 mg of 2 to a 10 ml eggplant flask.
After dissolving in 1 ml of THF, n-Bu ₄ NF (IM/
1.58 ml of THF) was added thereto, and 5 ml of ethyl acetate was added at room temperature (23°C) and mixed well to separate the organic and aqueous layers. The aqueous layer was extracted with ethyl acetate (5 ml x 2),
The organic layers were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was subjected to silica gel column chromatography (Merck silica gel 10 g; ethyl acetate: n-hexane = 1:4) to obtain 5 as a product.
71.7 mg (yield 84%) was obtained. IR (CHCl ₃ ): 3620-3280, 1730 cm ^-1 HNMR (CDCl ₃ , 90 MHz, ppm) δ: 0.88 (t, 3, 4.5 Hz, CH ₃ ), 1.1-2.5 (m, 37,
CH ₂ × 17, CH × 2, andOH), 3.3−4.5 (m,
10, OCH ₃ , CHO×3, and CH ₂ O×2), 4.5
-4.8 (m, 2, OCHO x 2), 5.45 (m, 2,
vinyl1) Thin layer chromatography: Rf: 0.54 (EtOAc-hexane = 1:4) Optical rotation: [α] [α] = +0.65° (C0.588, MeOH) Reference example 6 After taking 29.2 mg of 6 in a 5 ml test tube and dissolving it in 0.5 ml of THF, 0.45 ml of n-Bu ₄ NF (IM/THF) was added, and the mixture was stirred at room temperature (21° C., PM4:40) for 4 hours. After diluting with 2 ml of THF, 2 ml of saturated saline was added and mixed well. Add 5 ml of ethyl acetate, shake well, and separate the organic and aqueous layers. The aqueous layer was extracted with ethyl acetate (5 ml x 2). After concentration, it was subjected to silica gel column chromatography (Merck silica gel 1.5 g), and ethyl acetate: n-hexane = 1:
2), 20 mg of product 7 (yield 83%) was obtained. The properties of this product were the same as those of Reference Example 5 . Example 1 65.1 mg of 5 was placed in a 10 ml eggplant flask and prepared with 3 ml of acetone. Under a stream of argon, 55.4 ml of John's reagent was added dropwise at −30° C. using a microsyringe. After stirring at -30°C for 50 minutes, 3 ml of a saturated aqueous sodium bicarbonate solution was added and stirred vigorously. After the aqueous layer turned green, 10 ml of ethyl acetate and 10 ml of a saturated aqueous sodium bicarbonate solution were added, followed by vigorous shaking. The organic layers were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was subjected to silica gel column chromatography (Merck silica gel 7g; ethyl acetate:hexane = 1:2) to obtain 8 as a product.
64.7 mg (yield 99%) was obtained. IR (CHCl ₃ ): 1735 cm ^-1 ; HNMR (CDCl ₃ , 90 MHz, ppm) δ: 0.88 (t, 3, J = 6.0 Hz, CH ₃ ), 1.1-2.9 (m,
36, CH ₂ × 17and CH × 2), 3.3−4.8 (m, 11,
OCH ₃ , CHO×2, CH ₂ O×2and OCHO×
2), 5.3-5.6 (m, 2, vinyl1) TLC: Rf: 0.33 (Et OAc-hexane = 1:2) Optical rotation: [α] = 0.63° (C0.7575, MeOH) Example 2 Pour 11.6ml of 7 into a 5ml test tube and add 0.6ml of acetone.
Dissolved in ml. John's reagent was added dropwise with a syringe at −30° C. under an argon stream. After stirring at -30°C for 40 minutes, the mixture was diluted with 1 ml of ethyl acetate, 1 ml of saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred vigorously.
After the aqueous layer turns green, add 10 ethyl acetate
10 ml of saturated sodium bicarbonate was added and stirred vigorously. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with ethyl acetate (2 x 10 ml). The organic layers were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was subjected to silica gel column chromatography (Merck0.9
g; ethyl acetate:hexane=1:2), 11 mg (yield 95%) of 9 was obtained as a product. The properties of this product were the same as in Example 1. Example 3 8 (55.2 ml) to 7 ml of CH ₃ COOH−H ₂ O−
It was dissolved in THF (3:1:1) and stirred at 45°C for 10.7 hours. It was concentrated on a rotary evaporator and azeotroped with toluene (3 times). The concentrated solution was directly subjected to silica gel column chromatography (Merck silica gel 5 g; ethyl acetate: hexane = 1:1),
28.7 mg of PGD ₁ methyl ester 10 as product
(yield 76%). IR (CHCl ₃ ): 3720-3240, 1730 cm ^-1 HNMR (CDCl ₃ , 90 MHz, ppm) δ: 0.89 (t, 3, J = 6.4 Hz, CH ₃ ), 1.1-2.1 (m,
21, CH ₂ × 9, CH, and OH × 2), 2.32 (t,
2, J = 7.0Hz, CH ₂ COOC), 2.44 (d, 2, J
= 2.6Hz, CH ₂ C = O), 2.79 (dd, 1, J = 11.6
Hz, 7.0Hz, CHC = O), 3.67 (s, 3, OCH ₃ ),
4.08 (br, q, 1, J=6.2Hz, CHO), 4.51
(m, 1, CHO), 5.37 (dd, 1, J = 15.4, 7.0
Hz, Viny1), 5.63 (dd, 1, J=15.4, 6.2
Hz); CNMR (CDCl ₃ , 90MHz, ppm) δ 14.1, 22.7, 24.8, 25.2, 26.9, 28.0, 29.0,
29.5, 31.8, 34.0, 36.9, 47.9, 48.2, 51.5,
54.9, 68.1, 72.8, 126.6, 138.8, 174.4, 217.3 TLC: Rf: 0.64 (EtOAc-cyclohexane-THF=6:3:1) Optical rotation: [α] = +23.8° ( C 1.355, MeOH) Implementation Example 4 9 3.3 mg to 0.5 ml of AcOH-H ₂ O-THF (3:
1:1) and stirred at 45°C for 7 hours. The solvent was removed using a vacuum pump, the solvent was distilled off azeotropically with toluene (3 times), and then chromatographed using silica gel column chromatography (Merck
0.6g of silica gel; ethyl acetate:hexane=3:2)
2.0 mg of 11 (yield 88%)
Obtained. IR (CHCl ₃ ): 3720-3240, 740, 1730 cm ^-1 HNMR (CDCl ₃ , 90 MHz, ppm) δ: 0.89 (t, 3, J = 6.4 Hz, CH ₃ ), 1.1-2.1 (m,
21, CH ₂ × 9, CH, and OH × 2), 2.32 (t,
2, J = 7.0Hz, CH ₂ COOC), 2.44 (d, 2, J
= 2.6Hz, CH ₂ C = O), 2.79 (dd, 1, J = 11.6
Hz, 7.0Hz, CHC = O), 3.67 (s, 3, OCH ₃ ),
4.08 (br, q.1, J=6.2Hz, CHO), 4.51 (m,
1, CHO), 5.37 (dd, 1, J=15.4, 7.0Hz,
Viny1), 5.63 (dd, 1, J = 15.4, 6.2Hz); CNMR (CDCl ₃ , 90MHz, ppm) δ 14.1, 22.7, 24.8, 25.2, 26.9, 28.0, 29.0,
29.5, 31.8, 34.0, 36.9, 47.9, 48.2, 51.5,
54.9, 68.1, 72.8, 126.6, 138.8, 174.4, 217.3 Reference example 1 In a 100 ml eggplant flask under argon flow, -78
At ℃, add 20.4 ml of an equivalent toluene solution of 2,6-t-botyl-4-methylphenol and dineno-butylaluminum (0.146), stir, and dry.
12 dissolved in 6 ml of toluene was added in a stainless steel tube. After raising the temperature to -20℃ over 3 hours,
Stirred at -20°C for 25 hours. Dilute the reaction solution with ethyl acetate10
ml, 40 ml of saturated aqueous sodium hydrogen tartrate solution was added, and the mixture was thoroughly shaken. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with ethyl acetate.
(20ml x 2). The organic layers were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was subjected to silica gel column chromatography (Merck silica gel
15g; ethyl acetate: hexane: benzene = 1:7:1
→1:O:O), 121mg of 1 as product (yield 86
%)Obtained. IR (CHCl ₃ ): 3600−3320, 1725 cm ^-1 HNMR (CDCl ₃ , 90MHz, ppm) δ: 0.04 (s, 6, SiCH ₃ ×2), 0.7−1.1 (12, SiC
(CH ₃ ) ₃ and CH ₃ ), 1.1−2.7 (m, 31, CH ₂ ×
14, CH×2, and OH), 3.3−4.3(m, 8,
OCH ₃ , CHO×3and CH ₂ O), 4.67 (m, 1,
OCHO), 5.2-5.6 (m, 2, vinyl1) Reference example 2 Add 17 ml of the same reducing agent as in Reference Example 1 to a 10 ml test tube at -78°C under an argon stream and stir. there
13 dissolved in 2 ml of dry toluene was added in a stainless steel tube. After raising the temperature to -20℃ over 3 hours, add 0.83ml of reducing agent and heat at -20℃ for another 3 hours.
After stirring for an hour, 0.83 ml was added again, and the mixture was stirred for 2 hours and 30 minutes. After diluting the reaction solution with 5 ml of ethyl acetate, 10 ml of saturated sodium tartrate hydroxide solution was added and stirred thoroughly. After separating the organic and aqueous layers, the aqueous layer was extracted twice with ethyl acetate (2 x 10 ml), and the organic layers were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was subjected to silica gel column chromatography.
(Merck silica gel 3g; ethyl acetate: hexane: benzene = 1:7:1), 26 mg of product 3 (yield 76
%)Obtained. The properties of this product were the same as those of Reference Example 1.

Claims (1)

[Claims] 1 The following formula (1) In the formula, R ¹¹ represents a C ₁ to _{C 10} alkyl group or a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, and R ² and R ³ are the same or different and are hydrogen atoms, substituted or unsubstituted C ₁ to Represents a C ₁₀ alkyl group or a substituted or unsubstituted 5- to 6-membered cycloalkyl group, R ³¹
represents a tri(C ₁ to _{C 7} ) hydrocarbon silyl group,
R ⁴¹ represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group. Protected with a group that forms an acetal bond with the oxygen atom of the hydroxyl group at the 9-position of the prostaglandin F ₁ α group represented by the following formula (2) In the formula, R ¹¹ , R ² , R ³ , R ³¹ , R ⁴¹ are the same as above,
R ⁵¹ is the same as or different from R ⁴¹ and represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group. Protected prostaglandin expressed as
The following formula (3) is characterized in that F ₁ α is obtained, selectively deprotected, then oxidized, and then subjected to deprotection and/or hydrolysis reaction as necessary. In the formula, R ² and R ³ are the same as defined above, R ¹ is a hydrogen atom,
It represents a C ₁ -C ₁₀ alkyl group, and R ⁴ and R ⁵ are the same or different and represent a group that forms an acetal bond with a hydrogen atom or an oxygen atom of a hydroxyl group. Production method of prostagratein D type ₁ expressed as 2. The method for producing prostaglandin D ₁ according to claim 1, wherein the selective deprotection reaction is carried out using tetra-n-butylammonium fluoride. 3. A method for producing prostagladein D ₁ according to claim 1 or 2, wherein the oxidation reaction is carried out using a chromium oxygen oxidizing agent. 4. A new method for producing prostaglandin D ₁ according to any one of claims 1 to 3, wherein in the above formula (1), R ¹¹ is a methyl group or an ethyl group. 5. A new method for producing prostaglandin D ₁ type according to any one of claims 1 to 4, wherein in the above formula (1), R ³ is a hydrogen atom. 6 In the above formula (1), R ² is an n-pentyl group,
The method for producing prostaglandin D ₁ according to any one of claims 1 to 5, wherein the prostaglandin D 1 is an n-hexyl group, 2-methyl-1hexyl group, cyclohexyl group, or cyclopentyl group. 7. The method for producing prostaglandin D ₁ according to any one of claims 1 to 6, wherein R ³¹ in the above formula (1) is a triethylsilyl group or a t-butyldimethylsilyl group. 8 A patent in which R ⁴¹ and R ⁵¹ are the same or different and are a 2-tetrahydropyranyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, or (2-methoxyethoxy)methyl group in the above formula (2) A new method for producing prostaglandin D ₁ according to any one of claims 1 to 7.