阅读说明：本技术 鲁比前列酮(lubiprostone)的制备方法和其中间物 (Process for preparing LUBIPROSTONE (lubiprosone) and intermediates thereof ) 是由 魏士益 许敏冠 于 2019-07-10 设计创作，主要内容包括：本发明揭示一种用于制备鲁比前列酮(Lubiprostone)的新颖方法和经由该方法制得的新颖中间物。本发明方法不会产生难以移除的氢化副产物,因此能够以高效率且低成本的方式制造鲁比前列酮。(The present invention discloses a novel process for the preparation of Lubiprostone (Lubiprostone) and novel intermediates prepared by this process. The process of the present invention does not produce hydrogenation by-products that are difficult to remove, thus enabling lubiprostone to be produced in a highly efficient and cost effective manner.)

1. A process for the preparation of Lubiprostone (Lubiprostone), comprising the steps of:

(1) reacting a cyclopentenone of formula 1:

wherein R is₁Is C_1-7Alkyl, aryl or aralkyl, each unsubstituted or substituted by C_1-4Alkyl, nitro, halogen or alkoxy, and P₁Is a hydroxy protecting group coupled with a cuprate derived from a compound of formula 2 a:

wherein P is₂Is a hydroxyl protecting group, and X is Cl, Br or I, to form a compound of formula 3:

wherein R is₁、P₁And P₂As defined above;

(2) removing the P₂Radicalizing and oxidizing the hydroxyl group in the omega-side chain to form a compound of formula 5:

wherein R is₁And P₁As defined above; and

(3) removing the P₁And R₁A group.

2. A compound of formula 3:

wherein P is₁And P₂Independently is a hydroxy protecting group, and R₁Is C_1-7Alkyl, aryl or aralkyl, each unsubstituted or substituted by C_1-4Alkyl, nitro, halogen or alkoxy.

3. A compound of formula 2:

wherein P is₂Is a hydroxyl protecting group or H, and X is Cl, Br or I.

Technical Field

The present invention relates to a novel process for the preparation of lubiprostone and novel intermediates thereof.

Background

Lubiprostone is a medicine used for treating diseases such as chronic idiopathic constipation, constipation related to female irritable bowel syndrome and opioid-induced constipation

The active pharmaceutical ingredient in (1). The current method for the synthesis of lubiprostone in the prior art, such as disclosed in EP0430551, US 7812182, US 7928252, US 8309744, US 9382272 and CN 103787942, is the use of corilagolactone (Corey lactone) or its derivativesThe α -side chain and ω -side chain of lubiprostone were constructed separately as starting materials by a two-step Wittig reaction (Wittig reaction) as shown in scheme a below. However, the curie process requires at least 8 to 12 synthetic steps and thus has a low yield.

Procedure A

As shown in scheme B below, the methods disclosed in the prior art, such as US 9670234 and WO 2012048447, are by 1, 4-conjugate addition of cyclopentenone a with a vinyl boron compound or vinyl cuprate B to form intermediate C of lubiprostone having double bonds at C13-C14, C5-C6, and/or C17-C18; removing the benzyl protecting group via hydrogenation and reducing the double bond at C13-C14, C5-C6 and/or C17-C18 to a single bond to give compound D; and performing three additional chemical reactions to synthesize lubiprostone.

Procedure B

This method can form lubiprostone relatively quickly. However, since the steric hindrance on both sides of the double bond at the compound C13-C14 is so great that the intermediate C is extremely difficult to hydrogenate or reduce, it is necessary to use a large amount of expensive hydrogenation catalyst at high pressure and high temperature to reduce all double bonds to single bonds. In this case, by-products will inevitably be produced due to incomplete double bond reduction, and dehydration or deoxidation by-products, or even by-products with displaced double bonds, will also be produced due to extreme conditions. Since these by-products are very similar in polarity to the main products having single bonds, it is almost impossible to completely remove the hydrogenation by-products using silica gel chromatography, and thus this method faces great difficulties in purification for the manufacture of lubiprostone in industrial mass production.

Thus, there is a need for a process that can produce lubiprostone in high yield and high purity in a highly efficient and cost effective manner.

Disclosure of Invention

In one aspect, the present invention provides a novel method for preparing lubiprostone, which can effectively solve the aforementioned conventional problems.

The method for preparing lubiprostone comprises the following steps:

reacting a cyclopentenone of formula 1:

wherein R is₁Is C_1-7Alkyl, aryl or aralkyl, each unsubstituted or substituted by C_1-4Alkyl, nitro, halogen or alkoxy, and P₁Is a hydroxy protecting group coupled with a cuprate derived from a compound of formula 2 a:

wherein P is₂Is a hydroxyl protecting group, and X is Cl, Br or I to provide a compound of formula 3:

wherein R is₁、P₁And P₂As defined above;

removing P₂Radicalizing and oxidizing the hydroxyl group in the omega-side chain to form a compound of formula 5:

wherein R is₁And P₁As defined above; and removing P₁And R₁A group.

In another aspect, the present invention provides novel intermediates useful for the manufacture of lubiprostone in high purity and yield.

Detailed Description

As used herein, the singular forms [ a ] and [ the ] include the plural forms thereof unless specifically limited. The use of any and all examples, or exemplary language (such as) and (e) herein, is intended merely to more fully illuminate the invention and does not pose a limitation on the scope of the invention, nor is the language used in the specification to suggest that any non-claimed method or condition may pose a necessary feature in the practice of the invention.

Herein, unless otherwise specified, the term [ alkyl group "refers to a straight or branched chain aliphatic hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms in the chain, such as methyl, ethyl, n-propyl, isopropyl, tertiary butyl, and the like; the term [ alkoxy group "means a straight or branched chain alkoxy group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms in the chain, such as methoxy group, propoxy group, t-butoxy group, pentyloxy group, and the like; the term [ aryl "refers to monocyclic or polycyclic aromatic hydrocarbon groups such as phenyl, naphthyl, anthryl, phenanthryl, and the like; and the term [ aralkyl group "refers to a straight or branched chain hydrocarbon having 1 to 20 carbon atoms and one or more aryl groups as described above, such as benzyl, benzhydryl, fluorenylmethyl, and the like.

When the defined groups are substituted, the substituents may be selected from the group consisting of halogen, alkyl, aryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, alkylamino, arylamino, cyano, nitro, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, and carbonyl, or a heterocyclic group selected from the group consisting of: pyridyl, thienyl, pyranyl, furyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidyl, pyrrolidonyl, and the like, and combinations thereof.

In the description of the compounds herein, the solid wedge lineMeaning that the substituents are in the beta orientation (in the plane of the molecule or page)Upper) and a wedge-shaped dotted line

Indicating that the substituent is in the alpha orientation (below the plane of the molecule or page).

Preparation of lubiprostone

The present invention provides a process for the preparation of lubiprostone, as shown in scheme C below:

procedure C

As shown in step a of scheme C, the optically active cyclopentenones are represented by formula 1 (wherein R is₁Is C_1-7Alkyl, aryl or aralkyl, each unsubstituted or substituted by C_1-4Alkyl, nitro, halogen or alkoxy, and P₁Is a hydroxy protecting group) with a compound derived from formula 2 (wherein X is Cl, Br or I, and P₂Coupling of the omega-side chain units of the cuprate salt being a hydroxy protecting group or H) to prepare a compound of formula 3 (wherein R is₁Is C_1-7Alkyl, aryl or aralkyl, each unsubstituted or substituted by C_1-4Alkyl, nitro, halogen or alkoxy, and P₁And P₂Independently a hydroxyl protecting group); the coupling reaction is preferably carried out at a temperature in the range of about-100 ℃ to about 40 ℃.

Suitable hydroxy protecting groups (i.e., P)₁And P₂) Including, but not limited to, methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis (2-chloroethoxy) methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, trityl, allyl, benzyl, substituted benzyl, and SiR_aR_bR_cWherein R is_a、R_bAnd R_cEach independently is C_1-8Alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl. Preferably, a hydroxyl groupThe group protecting group includes a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, an n-octyldimethylsilyl group, a methoxymethyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group.

Step b of scheme C is directed to the selective removal of P from the omega-side chain of the compound of formula 3₂And (4) deprotection reaction of the protecting group. Conditions for carrying out deprotection reactions with P₂Are related to and readily apparent to those skilled in the art. For example, when P₁Is an acid-labile protecting group, such as tetrahydrofuranyl, and P₂When trialkylsilyl, the trialkylsilyl protecting group may be selectively removed under neutral or basic conditions by using fluoride ions, such as tetrabutylammonium fluoride.

Step C of scheme C is for the oxidation reaction. C15-OH in the compound of formula 4 is oxidized to a keto group using a TEMPO oxidation process under suitable oxidation conditions, such as Coriolis oxidation (Collinoxidation), Swern oxidation (Swern oxidation), pyridinium chlorochromate (PCC) oxidation, Pyridinium Dichromate (PDC) oxidation, and tetramethylpiperidine oxide (TEMPO) oxidation, preferably under TEMPO oxidation, to form the diketone of formula 5.

Steps d and e of Process C are directed to removing P₁Protecting group and removal of R₁Groups, and the order of the two steps may be interchanged.

As shown in scheme C, step d, the compound of formula 5 or 6a is subjected to a deprotection reaction to remove P₁A protecting group. Conditions for carrying out deprotection reactions with P₁Are related to and readily apparent to those skilled in the art. For example, when P₁When tetrahydropyranyl, the compound of formula 5 or 6a may be dissolved in a suitable solvent such as methanol or a solvent mixture of acetone and water in a volume ratio of about 5 to 1, treated with a deprotecting agent such as hydrogen chloride, p-toluenesulfonic acid or pyridine p-toluenesulfonic acid, and stirred at room temperature for about 10 minutes to about 10 hours; the reaction mixture may then be quenched with a base, such as ammonium hydroxide, and worked up in a conventional manner. When P is present₁In the case of unsubstituted or substituted benzyl, the solvent may be one of a suitable solventAnd the deprotection reaction is carried out by using a hydrogenation catalyst in the presence of hydrogen. Suitable hydrogenation catalysts comprise a metal selected from the group consisting of: palladium, platinum, rhodium, nickel and mixtures thereof. Examples of catalysts include, but are not limited to, Pd/C, Pt/C and Ni. Suitable solvents may be selected from tetrahydrofuran, ethyl acetate, methanol, ethanol, toluene and mixtures thereof.

As shown in scheme C, step e, the compound of formula 5 or 6b is subjected to a hydrolysis reaction to remove R₁A group. Conditions for carrying out the hydrolysis reaction with R₁Are related to and readily understood by those of skill in the art. For example, when R₁When alkyl, the compound of formula 5 or 6b may be subjected to an enzymatic hydrolysis reaction in the presence of an enzyme, preferably candida antarctica lipase, such as lipase 435, in an aqueous phase (water or buffer), and/or an organic solvent such as hexane, toluene, tetrahydrofuran, methyl isobutyl ketone, and mixtures thereof. When R is₁In the case of unsubstituted or substituted benzyl, the compound of formula 5 or 6b may be subjected to hydrogenation by reaction with hydrogen in a suitable solvent in the presence of a hydrogenation catalyst.

The novel process of the present invention requires fewer steps than conventional synthetic methods for lubiprostone. Surprisingly, the novel process of the present invention also allows the products to be prepared in higher yield, higher purity and at lower cost. In detail, in the conventional method of the aforementioned scheme B, a large amount of expensive hydrogenation catalyst is used; however, in the novel process of the present invention, the protecting group such as benzyl group can be removed rapidly only by using a small amount of hydrogenation catalyst in step d or e of scheme C. In addition, the novel method of the present invention can completely avoid the by-products generated in the conventional method of the process B, so that the disadvantages caused by the conventional method can be effectively solved.

Novel compounds of formula 3

The invention also relates to a novel compound of formula 3:

wherein P is₁And P₂Independently is a hydroxy protecting group, and R₁Is C_1-7Alkyl, aryl or aralkyl, each unsubstituted or substituted by C_1-4Alkyl, nitro, halogen or alkoxy.

Novel compounds of formula 2

The invention further relates to a novel compound of formula 2:

wherein P is₂Is a hydroxyl protecting group or H, and X is Cl, Br or I.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Examples of the invention

Example 1

4, 4-difluoro-3-keto-octanoic acid ethyl ester

A 20 liter four-necked flask was flame dried and cooled under nitrogen. Diisopropylamine (585g, 5.78mol) dissolved in 4.7L anhydrous tetrahydrofuran was added to the reaction flask followed by dropwise addition of n-butyllithium (3.6L, 1.6M in hexanes) at-70 ℃ and stirring for 1 hour. Subsequently, ethyl acetate (509g, 5.78mol) was slowly added to the lithium reagent. After 30 minutes, ethyl 2, 2-difluorohexanoate (520g, 2.89mol) was added to the reaction flask at-70 ℃. The reaction mixture was stirred for 30 minutes, and checked for reactivity using Thin Layer Chromatography (TLC). The mixture was quenched with 5L of saturated aqueous ammonium chloride and stirred for 10 minutes. The mixture was phase separated and the aqueous layer was extracted with 1L of toluene. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum to give 875g of crude ester product.

¹H-NMR(CDCl₃)：δ11.957(s，0.5H)，5.444(s，0.5H)，4.150～4.240(m，2H)，3.648(s，1H)，1.953～2.034(m，2H)，1.223～1.414(m，7H)，0.861(dt，3H)

¹³C-NMR(CDCl₃)：δ193.659(t)，172.168，167.352(t)，165.754，118.535(t)，118.091(t)，90.060(t)，61.623，60.883，43.357，34.048(t)，31.938(t)，23.805(t)，23.046(t)，22.279，22.192，13.941，13.873，13.607，13.546

Example 2

4, 4-Difluorooctane-1, 3-diol

At ambient temperature, sodium borohydride (253g, 6.69mol) was added to dissolve the crude ester product of example 1 (875g) in 4.5L ethanol. The reaction mixture was stirred for 2 hours and checked for reactivity using TLC. Subsequently, the reaction mixture was adjusted to a neutral solution with 3N aqueous hydrochloric acid. The aqueous solution was concentrated and ethanol was removed. The aqueous solution was extracted twice with 2.5L of ethyl acetate. The organic layer was concentrated under vacuum. The crude 1, 3-diol product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exsolution. The yield of the 1, 3-diol compound was 306g (58%, two steps).

¹H-NMR(CDCl₃)：δ3.760～3.893(m，5H)，1.678～1.922(m，4H)，1.291～1.505(brs，4H)，0.897(t，3H)

¹³C-NMR(CDCl₃)：δ123.997(t)，71.396(t)，60.040，32.040(t)，31.561，23.379(t)，22.461，13.777

Example 3

4.4-difluoro-1-iodooct-3-ol

A 12 liter four-necked flask was flame dried and cooled under nitrogen. 4, 4-Difluorooctane-1, 3-diol from example 2 dissolved in 6L of anhydrous THF(607g, 3.33mol) was added to the reaction flask. Imidazole (803g, 11.8mol) and triphenylphosphine (2.2kg, 8.4mol) were added to the flask. In a homogeneous mixture, iodine (2.56kg, 10.1mol) was added to the reaction flask at 0 ℃ and stirring was continued for 3 hours. Then, the mixture was washed with 20% Na₂S₂O₃The reaction mixture was quenched with aqueous solution and 3L of ethyl acetate was added and stirred for 30 minutes. The reaction mixture was subjected to phase separation. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude iodine product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exhibitor. The yield of the iodine compound was 737g (75%).

¹H-NMR(CDCl₃)：δ3.858(q，1H)，3.363～3.406(m，1H)，3.267～3.319(m，1H)，2.211(br s，1H)，2.083～2.151(m，1H)，1.761～2.013(m，3H)，1.462～1.527(m，2H)，1.328～1.402(m，2H)，0.924(t，3H)

¹³C-NMR(CDCl₃)：δ123.786(t)，72.748(t)，33.634，32.168(dd)，23.336(t)，22.481，13.786，1.893

Example 4

(4, 4-difluoro-1-iodooct-3-yloxy) -trimethylsilane

4, 4-difluoro-1-iodooctan-3-ol of example 3 (737g, 2.5mol) dissolved in 7.4L ethyl acetate was added to a 12 liter four-necked flask followed by imidazole (2.58kg, 3.79 mol). Trimethylsilyl chloride (326g, 3mol) was added to this flask in a homogeneous mixture. The white solid was filtered from the reaction mixture and washed with 3.5L of saturated NaHCO₃The filtrate was extracted twice with aqueous solution. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude silane product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exhibitor. The yield of the silane compound was 780g (85%).

¹H-NMR(CDCl₃)：δ3.846～3.908(m，1H)，3.290～3.331(m，1H)，3.117～3.168(m，1H)，1.635～2.060(m，4H)，1.312～1.507(m，4H)，0.914(t，3H)，0.173(br s，9H)

¹³C-NMR(CDCl₃)：δ123.817(t)，73.977(dd)，34.967(dd)，32.450(t)，23.115(t)，22.542，13.794，2.313，0.222

Example 5

(4, 4-difluoro-1-iodooct-3-yloxy) -triethylsilane

4, 4-difluoro-1-iodooctan-3-ol of example 3 (174g, 0.60mol) dissolved in 1.8L ethyl acetate was added to a 5 liter four-necked flask followed by imidazole (61.3g, 0.90 mol). To this flask was added triethylsilane chloride (109g, 0.72mol) in a homogeneous mixture. Next, the white solid was filtered from the reaction mixture and washed with 1.5L of saturated NaHCO₃The filtrate was extracted twice with aqueous solution. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude silane product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exhibitor. The yield of the silane compound was 182g (75%).

¹H-NMR(CDCl₃)：δ3.850～3.890(m，1H)，3.318(br s，1H)，3.157～3.217(m，1H)，1.261～2.084(m，8H)，0.908～0.996(m，12H)，0.647～0.704(m，6H)

¹³C-NMR(CDCl₃)：δ124.000(t)，74.035(dd)，36.000(d)，31.292(t)，23.087(t)，22.590，13.831，6.795，5.000，1.986

Example 6

7- (3R-hydroxy-5-keto-cyclopent-1-enyl) -heptanoic acid phenylmethyl ester

Dissolving 7-(3R-hydroxy-5-keto-cyclopent-1-enyl) heptanoic acid (50g, 0.22mol) was added to a 1 liter three-necked round bottom flask followed by potassium carbonate (91.2g, 0.66mol) and benzyl chloride (55.7g, 0.44 mol). The reaction mixture was heated at 50 ℃ to 60 ℃ for 1 hour. After cooling the mixture at room temperature, the solid was filtered off and the filtrate was extracted twice successively with 500ml of water. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude ester product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exhibitor. The yield of the benzyl compound was 56g (80%).

¹H-NMR(CDCl₃)：δ7.313～7.360(m，5H)，7.125～7.131(m，1H)，5.103(s，2H)，4.930(br s，1H)，2.797(dd，1H)，2.143～2.362(m，5H)，1.300～1.649(m，9H)

¹³C-NMR(CDCl₃)：δ206.267，173.674，155.841，147.96，136.023，128.554，128.201，128.182，68.519，66.147，44.871，34.215，28.848，28.731，27.141，24.757，24.325

Example 7

7- (3R-hydroxy-5-keto-cyclopent-1-enyl) -heptanoic acid 4-methoxybenzyl ester

7- (3R-hydroxy-5-keto-cyclopent-1-enyl) heptanoic acid (50g, 0.22mol) dissolved in 500ml DMF was added to a 1 liter three-necked round bottom flask followed by potassium carbonate (91.2g, 0.66mol) and 4-methoxybenzyl chloride (68.9g, 0.44 mol). The reaction mixture was heated at 50 ℃ to 60 ℃ for 1 hour. After cooling the mixture at room temperature, the solid was filtered off and the filtrate was extracted twice successively with 500ml of water. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude ester product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exhibitor. The yield of the ester compound was 57g (74%).

¹H-NMR(CDCl₃)：δ7.285(d，2H)，7.148～7.1510(m，1H)，6.884(d，2H)，5.034(s，2H)，4.912～4.922(m，1H)，3.797(s，3H)，2.782(dd，1H)，2.279～2.328(m，3H)，2.147(t，2H)，1.295～1.622(m，9H)

¹³C-NMR(CDCl₃)：δ206.663，173.736，159.363，156.354，147.451，129.896，127.919，113.749，68.131，65.835，55.115，44.674，34.084，28.684，28.546，26.971，24.583，24.135

Example 8

7- [ 5-keto-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] heptanoic acid phenylmethyl ester

Benzyl 7- (3R-hydroxy-5-keto-cyclopent-1-enyl) -heptanoate of example 6 (56g, 0.18mol) dissolved in 500ml of Dichloromethane (DCM) was added to a 1 liter three-necked round bottom flask followed by 2, 3-dihydrofuran (15g, 0.22mol) and a catalytic amount of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred for 1 hour. With saturated NaHCO₃The aqueous solution quenches the reaction mixture and then the phases are separated. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 63g (92%).

¹H-NMR(CDCl₃)：δ7.308～7.377(m，5H)，7.198～7.202(m，0.5H)，7.152～7.156(m，0.5H)，5.333～5.341(m，0.5H)，5.269～5.275(m，0.5H)，5.110(s，2H)，4.817～4.827(m，0.5H)，4.733～4.743(m，0.5H)，3.878～3.947(m，2H)，2.764(ddd，1H)，2.289～2.391(m，3H)，2.146～2.173(m，2H)，1.625～1.991(m，4H)，1.312～1.488(m，8H)

¹³C-NMR(CDCl₃)：δ206.548(205.923)，173.482，155.695(153.694)，148.267(147.715)，135.967，128.447，128.095，128.083，104.052(103.546)，73.274(72.722)，67.169(67.008)，65.996，43.762(42.106)，34.134，32.532(32.440)，28.875(28.860)，28.707(28.699)，27.066(27.036)，24.701(24.682)，24.357(24.341)，23.299

Example 9

7- [ 5-keto-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] -heptanoic acid 4-methoxybenzyl ester

4-Methoxybenzenesilyl 7- (3R-hydroxy-5-keto-cyclopent-1-enyl) -heptanoate (150g, 0.43mol) of example 7 dissolved in 1.5L DCM was added to a 3 liter three-necked round bottom flask followed by 2, 3-dihydrofuran (45g, 0.65mol) and catalytic amount of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred for 1 hour. With 100ml of saturated NaHCO₃The aqueous solution quenches the reaction mixture and then the phases are separated. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 170g (94%).

¹H-NMR(CDCl₃)：δ7.245～7.275(m，2H)，7.173～7.177(m，0.5H)，7.127～7.131(m，0.5H)，6.838～6.862(m，2H)，5.301～5.309(m，0.5H)，5.235～5.243(m，0.5H)，5.010(s，2H)，4.781～4.792(m，0.5H)，4.699～4.708(m，0.5H)，3.845～3.916(m，2H)3.767(s，3H)，2.727(dd，1H)，2.254～2.357(m，3H)，2.125(t，2H)，1.805～2.009(m，4H)，1.590(t，2H)，1.445(t，2H)，1.272～1.296(m，4H)

¹³C-NMR(CDCl₃)：δ206.449(205.835)，173.448，159.344，155.637(153.652)，148.106(147.562)，129.854，128.329，127.972，113.684(113.607)，103.922(103.427)，73.163(72.623)，67.039(66.878)，65.693，55.038，43.636(41.976)，34.046，32.410(32.321)，28.753(28.738)，28.573(28.561)，26.952(26.921)，24.587(24.568)，24.230(24.219)，23.192(23.184)

Example 10

7- (3R-Benzyloxy-5-keto-cyclopent-1-enyl) -heptanoic acid phenylmethyl ester

Benzyl 7- (3R-hydroxy-5-keto-cyclopent-1-enyl) -heptanoate of example 6 (50g, 0.16mol) dissolved in 500ml of DMF was added to a 1 liter three-necked round-bottom flask at 0 ℃ and sodium hydride (7.1g, 0.18mol) was added to the flask while stirring for 30 minutes. Then benzyl bromide (41g, 0.24mol) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for 1 hour and cooled to-10 ℃. 250ml of saturated aqueous NaCl solution were added to the mixture and the mixture was extracted with 500ml of ethyl acetate. The organic layer was over anhydrous MgSO₄The solid was filtered off and the solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 45g (70%).

¹H-NMR(CDCl₃)：δ7.296～7.370(m，10H)，7.186～7.198(m，1H)，5.114(s，2H)，4.571～4.679(m，3H)，2.711(dd，1H)，2.330～2.418(m，3H)，2.171(t，2H)，1.68～1.60(m，2H)，1.49～1.44(m，2H)，1.261～1.676(m，8H)

¹³C-NMR(CDCl₃)：δ205.709，173.541，153.803，148.490，137.677，136.102，128.565，128.543，128.178，127.992，127.882，74.974，71.722，66.086，42.219，34.237，28.947，28.791，27.171，24.788，24.469

Example 11

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-trimethylsilyloxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoic acid phenylmethyl ester

A 3 liter three-neck flask was flame dried and then cooled under nitrogen. (4, 4-difluoro-1-iodooct-3-yloxy) -trimethylsilane of example 4 (56.6g, 0) was added at-70 ℃.16mol) and 570ml of diethyl ether were added to the reaction flask, followed by dropwise addition of a third butyllithium (190ml, 16% in pentane). A suspension of copper cyanide (copper cyanide, 7.2g, 0.08mol) in 280ml of diethyl ether was cooled to-70 ℃ and added to the reaction flask while stirring for 30 minutes. Next, 7- [ 5-keto-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] of example 8 is reacted at-70 deg.C]A solution of benzyl heptanoate (19.3g, 0.05mol) in 200ml of diethyl ether was added to the reaction mixture and the mixture was warmed to 0 ℃. The reaction mixture was quenched with 450ml of saturated aqueous ammonium chloride solution containing 50ml of ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and passed over anhydrous MgSO₄And (4) dehydrating. The solid was filtered off and the organic solvent was evaporated off under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 29g (92%).

¹H-NMR(CDCl₃)：δ7.271～7.308(m，5H)，5.171(br s，1H)，5.071(s，2H)，3.664～4.078(m，4H)，2.700～2.713(m，1H)，1.200～2.317(m，29H)，0.895(t，3H)，0.113(s，9H)

¹³C-NMR(CDCl₃): δ 216.527(215.661), 172.903, 135.886, 128.115, 127.810, 127.774, 124.999(t), 104.191, 101.403(101.345), 78.213, 74.517(74.170), 66.713(66, 663), 66.549(66.465), 53.274(53.134), 52.960(52.705), 46.130(46.097), 45.915(45.882), 43.531(43.498), 33.780, 32.179, 30.760(t), 29.061, 28.591, 26.248, 24.499, 23.030, 22.841, 22.280, 13.519, -0.052 of example 12

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-trimethylsilyloxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoic acid 4-methoxybenzyl ester

A 12 liter four-necked flask was flame dried and then cooled under nitrogen. (4, 4-difluoro-1-iodooctan-) -of example 4 at-70 deg.C3-yloxy) -trimethylsilane (393.4g, 1.08mol) and 4L of diethyl ether were added to the reaction flask, followed by dropwise addition of a third butyllithium (1.3L, 16% in pentane). A suspension of copper cyanide (48.4g, 0.54mol) in 1L of diethyl ether was cooled to-70 ℃ and added to the reaction flask while stirring for 30 minutes. Next, 7- [ 5-keto-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] of example 9 is reacted at-70 deg.C]A solution of 4-methoxybenzyl heptanoate (150g, 0.36mol) in 1.5L diethyl ether was added to the reaction mixture and the mixture was warmed to 0 ℃. The reaction mixture was quenched with 2.7L of saturated aqueous ammonium chloride solution containing 300ml of ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and passed over anhydrous MgSO₄And (4) dehydrating. The solid was filtered off and the organic solvent was evaporated off under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 190g (80%).

¹H-NMR(CDCl₃)：δ7.259～7.291(m，2H)，6.867～6.890(m，2H)，5.100～5.200(m，1H)，5.031(s，2H)，3.617～3.927(m，7H)，0.851～2.788(m，33H)，0.009(s，9H)

¹³C-NMR(CDCl₃): δ 217.510(216.607), 173.668, 159.557, 130.031, 128.217, 124.369, 121.917, 113.909, 104.634(104.558), 84.762, 74.978(74.606), 72.534, 66.940(66.885), 53.778(53.596), 52.442(52.156), 46.997(46.431), 44.700(43.926), 34.279, 32.389, 31.129(t), 29.459, 29.262, 28.707(28.472), 27.559, 26.863(26.620), 24.874, 23.364, 23.144, 22.635, 13.884, 0.547 example 13

7- [ (1R,2R,3R) -3-Phenylmethyloxy-2- (4, 4-difluoro-3-trimethylsilyloxyoctyl) -5-keto-cyclopentyl ] heptanoic acid phenylmethyl ester

A 1 liter three-neck flask was flame dried and then cooled under nitrogen. (4, 4-difluoro-1-iodo) of example 4 at-70 deg.COct-3-yloxy) -trimethylsilane (27.3g, 75mmol) and 270ml of diethyl ether were added to the reaction flask, followed by dropwise addition of a third butyllithium (90ml, 16% in pentane). A suspension of copper cyanide (3.36g, 38mmol) in 70ml of diethyl ether was cooled to-70 ℃ and added to the reaction flask while stirring for 30 minutes. Next, 7- [ 5-yl-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] of example 8 is reacted at-70 deg.C]A solution of benzyl heptanoate (10g, 25mmol) in 100ml of diethyl ether was added to the reaction mixture and the mixture was warmed to 0 ℃. The reaction mixture was quenched with 270ml of saturated aqueous ammonium chloride solution containing 30ml of ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and passed over anhydrous MgSO₄And (4) dehydrating. The solid was filtered off and the organic solvent was evaporated off under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 13g (81%).

¹H-NMR(CDCl₃)：δ7.325～7.364(m，10H)，5.118(s，2H)，4.453～4.584(m，2H)，3.304～4.043(m，2H)，0.911～2.702(m，29H)，0.113～0.145(m，9H)

¹³C-NMR(CDCl₃)：δ217.474(216.749)，173.541，137.860(t)，136.133，128.531，128.478，128.387，128.163，127.822，127.772，127.715，79.308(79.103)，71.631(70.936)，70.887(70.386)，66.052，53.744(53.684)，50.519(50.473)，46.553(46.443)，44.222(43.976)，34.268，33.399，32.526，29.414，28.928，27.805，27.710，27.577(20.501)，24.905(24.882)，22.628，13.519，0.328

Example 14

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-triethylsilanyloxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoic acid phenylmethyl ester

A 1 liter three-neck flask was flame dried and then cooled under nitrogen. At-70 deg.C, the compound of example 5(4, 4-difluoro-1-iodooct-3-yloxy) -triethylsilane (36.5g, 0.09mol) and 360ml of diethyl ether were added to the reaction flask, followed by dropwise addition of a third butyllithium (110ml, 16% in pentane). A suspension of cuprous cyanide (4.5g, 0.05mol) in 90ml of diethyl ether was cooled to-70 ℃ and added to the reaction flask while stirring for 30 min. Next, 7- [ 5-keto-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] of example 8 is reacted at-70 deg.C]A solution of benzyl heptanoate (11.6g, 0.03mol) in 120ml of diethyl ether was added to the reaction mixture and the mixture was warmed to 0 ℃. The reaction mixture was quenched with 270ml of saturated aqueous ammonium chloride solution containing 30ml of ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and passed over anhydrous MgSO₄And (4) dehydrating. The solid was filtered off and the organic solvent was evaporated off under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 16.6g (87%).

¹H-NMR(CDCl₃)：δ7.250～7.378(m，5H)，5.192～5.202(m，0.5H)，5.110(s，2H)，4.078～4.120(m，0.5H)，3.720～3.912(m，4H)，2.692～2.787(m，1H)，2.333(t，2H)，1.195～2.267(m，27H)，0.901～0.974(m，12H)，0.572～0.676(m，6H)

¹³C-NMR(CDCl₃)：δ217.495(216.599)，173.569，136.081，128.521，128.376，128.156，124.475(t)，104.649(101.757)，78.553，74.054(74.530)，67.715(66，925)，66.060(t)，53.862(53.505)，53.399(53.148)，46.454(t)，43.972(43.926)，34.233，32.503，30.863(30.628)，29.391，28.958，28.578，28.427(28.328)，26.613，24.882，23.349，23.083(23.045)，22.650，13.891，6.840，4.957

Example 15

4-Methoxyphenylmethyl 7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-triethylsiloxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoate

A 1 liter three-neck flask was flame dried and then cooled under nitrogen. (4, 4-difluoro-1-iodooct-3-yloxy) -triethylsilane from example 5 (36.5g, 0.09mol) and 360ml of diethyl ether were added to the reaction flask at-70 ℃ followed by dropwise addition of a third butyllithium (110ml, 16% in pentane). A suspension of copper cyanide (4.5g, 0.05mol) in 1L of diethyl ether was cooled to-70 ℃ and added to the reaction flask while stirring for 30 minutes. Next, 7- [ 5-keto-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] of example 9 is reacted at-70 deg.C]A solution of 4-methoxybenzyl heptanoate (12.5g, 0.03mol) in 125ml of diethyl ether was added to the reaction mixture and the mixture was warmed to 0 ℃. The reaction mixture was quenched with 270ml of saturated aqueous ammonium chloride solution containing 30ml of ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and passed over anhydrous MgSO₄And (4) dehydrating. The solid was filtered off and the organic solvent was evaporated off under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 18g (86%).

¹H-NMR(CDCl₃)：δ7.282(d，2H)，6.878(d，2H)，5.080～5.211(m，1H)，5.029(s，2H)，4.057～4.102(m，0.5H)，3.716～3.872(m，6H)，2.689～2.786(m，0.5H)，2.298(t，2H)，1.232～2.243(m，28H)，0.872～0.951(m，12H)，0.548～0.653(m，6H)

¹³C-NMR(CDCl₃)：δ217.607(216.675)，173.698，159.542，130.061，128.179，124.490(t)，113.894，104.656(101.742)，78.538，75.039(74.508)，67.107(66.885)，65.908，55.243，54.203(53.502)，46.659(46.416)，43.987，34.286，32.586(32.389)，30.848(t)，29.504，28.973，28.571，28.419(28.396)，28.305(28.275)，26.430，24.890，23.349，23.075(23.045)，22.658，13.913，6.855，4.950

Example 16

7- [ (1R,2R,3R) -3-Benzyloxy-2- (4, 4-difluoro-3-triethylsilanyloxyoctyl) -5-keto-cyclopentyl ] heptanoic acid phenylmethyl ester

A 1 liter three-neck flask was flame dried and then cooled under nitrogen. (4, 4-difluoro-1-iodooct-3-yloxy) -triethylsilane from example 5 (30.5g, 75mmol) and 300ml of diethyl ether were added to the reaction flask at-70 ℃ followed by dropwise addition of a third butyllithium (108ml, 16% in pentane). A suspension of copper cyanide (3.36g, 38mmol) in 70ml of diethyl ether was cooled to-70 ℃ and added to the reaction flask while stirring for 30 minutes. Next, 7- [ 5-keto-3R- (tetrahydrofuran-2-yloxy) -cyclopent-1-enyl ] of example 8 is reacted at-70 deg.C]A solution of benzyl heptanoate (10g, 25mmol) in 100ml of diethyl ether was added to the reaction mixture and the mixture was warmed to 0 ℃. The reaction mixture was quenched with 270ml of saturated aqueous ammonium chloride solution containing 30ml of ammonium hydroxide. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and passed over anhydrous MgSO₄And (4) dehydrating. The solid was filtered off and the organic solvent was evaporated off under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 13g (76%).

¹H-NMR(CDCl₃)：δ7.235～7.373(m，10H)，5.106(s，2H)，4.456～4.566(m，2H)，3.641～4.007(m，2H)，1.013～2.683(m，29H)，0.883～0.953(m，12H)，0.552～0.685(m，6H)

¹³C-NMR(CDCl₃)：δ217.669(216.948)，173.615，137.804(t)，136.073，128.551，128.483，128.194，127.845，127.784，127.724，127.602，79.381(79.161)，71.654，70.910，66.098，53.809(53.672)，50.598(50.507)，46.507(46.446)，44.382(44.275)，41.937，34.522，30.848(30.711)，30.036(29.854)，29.383，29.072(29.034)，28.966，27.854，26.757，24.897，24.214，23.394，23.075，22.658，13.944，6.870，4.912

Example 17

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-hydroxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) -cyclopentyl ] heptanoic acid phenylmethyl ester

The benzyl 7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-trimethylsilyloctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] -heptanoate of example 11 (44g, 70.4mmol) was dissolved in MeOH (440ml), followed by addition of formic acid (11ml) and distilled water (44ml) and stirring at room temperature for 3 hours. The reaction mixture was poured into 500ml of a saturated aqueous sodium bicarbonate solution and stirred for 30 minutes. The reaction mixture was concentrated and the aqueous layer was extracted with 500ml of ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 30g (77%).

¹H-NMR(CDCl₃)：δ7.237～7.316(m，5H)，5.038～5.169(m，3H)，3.659～4.070(m，4H)，0.874～2.725(m，34H)

¹³C-NMR(CDCl₃)：δ217.236(216.252)，173.120，135.695，128.030，127.641，124.053(t)，103.985(101.496)，78.420，75.115(74.840)，66.695(66.374)，65.542，53.550(52.992)，46.137(45.595)，45.527(45.389)，43.527，33.679，32.130(32.046)，31.672(31.534)，28.657，28.344，27.931(27.786)，26.870(26.588)，26.000，23.394，24.328，23.069(22.947)，22.176，13.428

Example 18

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-hydroxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] -heptanoic acid 4-methoxybenzyl ester

4-Methoxybenzyl 7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-trimethylsilyl-octyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoate of example 12 (169g, 0.26mol) was dissolved in MeOH (1.7L), followed by addition of formic acid (42ml) and distilled water (170ml) and stirring at room temperature for 3 hours. The reaction mixture was poured into 2L of saturated aqueous sodium bicarbonate and stirred for 30 minutes. The reaction mixture was concentrated and the aqueous layer was extracted with 2L of ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 138g (91%).

¹H-NMR(CDCl₃)：δ7.266(d，2H)，6.864(d，2H)，5.093～5.225(m，1H)，5.017(s，2H)，3.601～3.960(m，6H)，2.696～2.811(m，1H)，1.184～2.307(m，31H)，0.910(t，3H)

¹³C-NMR(CDCl₃)：δ217.633(216.620)，173.830，159.515，130.011，126.820，124.387(t)，113.867，104.504(102.022)，78.910，75.494(75.399)，67.456(66.921)，65.912，55.209，53.866(t)，46.663(45.790)，44.055，34.203，32.560(32.469)，32.363(32.120)，29.991(29.660)，29.330(29.262)，29.019，28.780，28.742，28.180(t)，26.996(26.822)，24.712(t)，23.493(23.399)，22.176，13.428

Example 19

7- [ (1R,2R,3R) -3-Benzyloxy-2- (4, 4-difluoro-3-hydroxyoctyl) -5-keto-cyclopentyl ] heptanoic acid phenylmethyl ester

Benzyl 7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-trimethylsilyloctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoate of example 11 (13g, 19mmol) was dissolved in MeOH (130ml), followed by addition of formic acid (3.3ml) and distilled water (13ml) and stirring at room temperature for 3 hours. The reaction mixture was poured into 150ml of saturated aqueous sodium bicarbonate solution and stirred for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with 150ml ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 10g (86%).

¹H-NMR(CDCl₃)：δ7.310～7.347(m，10H)，5.103(s，2H)，4.445～4.591(m，2H)，3.669～4.035(m，2H)，1.154～2.868(m，27H)，0.904～0.937(t，3H)

¹³C-NMR(CDCl₃)：δ217.918(216.897)，173.818，137.966(137.734)，137.344(136.034)，128.554，128.497，128.190，128.102，127.884，127.586，124.353(t)，79.479(79.418)，72.872(72.561)，71.680(70.841)，66.181(66.147)，65.912，54.386(53.908)，50.541，45.999(44.420)，43.384(41.885)，34.226，31.835(31.101)，29.308(29.118)，28.818(28.484)，27.622(27.254)，26.556(26.503)，24.806(24.723)，24.036(23.429)，22.742(22.598)，13.926

Example 20

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-keto-octyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoic acid benzyl ester

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-hydroxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) -cyclopentyl-example 17 dissolved in 300ml of toluene]Benzyl heptanoate (30g, 54mmol) was added to a 1 liter three-necked flask followed by TEMPO (1.72g, 11mmol), 3% NaHCO₃Aqueous solution (117ml) and potassium bromide (6.43g, 54 mmol). The reaction mixture was cooled to 0 ℃ and 12% NaOCl (42ml) was added dropwise to the flask. With Na₂S₂O₃The resulting brown solution was quenched with aqueous solution and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient. The yield of the title compound was 24g (80%).

¹H-NMR(CDCl₃)：δ7.183～7.302(m，5H)，5.084～5.169(m，1H)，5.019(s，2H)，4.285～4.309(m，1H)，3.709～3.771(m，2H)，1.166～3.017(m，30H)，0.826(t，3H)

¹³C-NMR(CDCl₃)：δ216.063，173.563，135.979，128.446，128.071，124.549，102.604(102.382)，80.084，67.183(66.867)，66.001，59.098(57.611)，48.748(48.662)，41.915(40.421)，34.173，32.600(32.471)，31.417(31.354)，30.476(t)，29.062(29.029)，28.931，28.232，26.774，24.759，24.643，23.485(23.242)，22.922，22.473，13.823

Example 21

4-Methoxybenzyl 7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-oxo-octyl) -5-oxo-3- (tetrahydrofuran-2-yloxy) cyclopentyl ] heptanoate

7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-hydroxyoctyl) -5-keto-3- (tetrahydrofuran-2-yloxy) -cyclopentyl-example 18 dissolved in 900ml of toluene]4-Methoxybenzyl heptanoate (90g, 154mol) was added to a 2l three-necked flask, followed by TEMPO (4.68g, 30mmol), 3% NaHCO₃Aqueous solution (324ml) and potassium bromide (17.4g, 150 mmol). The reaction mixture was cooled to 0 ℃ and 12% NaOCl (162ml) was added dropwise to the flask. With Na₂S₂O₃The resulting brown solution was quenched with aqueous solution and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 70g (78%).

¹H-NMR(CDCl₃)：δ7.277(d，2H)，6.873(d，2H)，5.084～5.176(m，1H)，5.026(s，2H)，3.774～4.095(m，6H)，2.729～2.916(m，3H)，2.299(t，2H)，2.145(ddd，1H)，1.213～2.030(m，24H)，0.892(t，3H)

¹³C-NMR(CDCl₃)：δ216.772(215.732)，201.599(201.075)176.175，159.541，130.038，128.216，118.387，113.893，104.686(101.943)，79.293(75.323)，67.426(67.024)，65.881，55.259，54.063(53.528)，46.841(45.410)，45.296(44.059)，34.272，34.131(34.006)，32.579(32.556)，32.287(32.013)，29.471(29.452)，28.901，27.960(27.858)，26.442，25.725，24.852，23.459，23.323(23.258)，22.408，13.751

Example 22

7- [ (1R,2R,3R) -3-Benzyloxy-2- (4, 4-difluoro-3-keto-octyl) -5-keto-cyclopentyl ] heptanoic acid phenylmethyl ester

7- [ (1R,2R,3R) -3-Phenylmethoxy) -2- (4, 4-difluoro-3-hydroxyoctyl) -5-keto-cyclopentyl from example 19 dissolved in 100ml of toluene]Benzyl heptanoate (10g, 17.5mmol) was added to a 500mL three-necked flask followed by TEMPO (0.55g, 3.5mmol), 3% NaHCO₃Aqueous solution (38ml) and potassium bromide (2.1g, 17.5 mmol). The reaction mixture was cooled to 0 ℃ and 12% NaOCl (19ml) was added dropwise to the flask. With Na₂S₂O₃The resulting brown solution was quenched with aqueous solution and extracted with ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 9g (90%).

¹H-NMR(CDCl₃)：δ7.294～7.357(m，10H)，5.108(s，2H)，4.423～4.556(m，2H)，3.782～3.952(m，1H)，2.900(t，1H)，2.738(t，1H)，1.197～2.691(m，24H)，0.889～0.938(m，3H)

¹³C-NMR(CDCl₃)：δ216.973(215.831)，201.166(200.661)，173.583，137.818(137.617)，136.125，128.535，128.171，127.943，127.875，127.605，118.501(118.417)，79.658，71.767(70.982)，66.056，54.048，50.583，45.475(44.473)，43.475(42.021)，34.313(34.230)，32.279(32.154)，29.425(29.300)，28.898，28.268(27.376)，26.545(25.881)，24.863，24.245，23.296(23.216)，22.400(22.389)，19.858，13.770

Example 23

Benzyl 7- [ (2R, 4aR, 5R, 7aR) -2- (1, 1-difluoropentyl) -octahydro-2-hydroxy-6-oxo-cyclopenta [ b ] pyran-5-yl) heptanoate

Benzyl 7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-keto-octyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl) heptanoate of example 20 (24g, 44mmol) dissolved in 240ml of acetonitrile was added to a 1 liter three-necked flask, followed by addition of distilled water (24ml) and 3N HCl (2.4ml) and stirring at room temperature for 1 hour. The reaction mixture was poured into 100ml of saturated aqueous sodium bicarbonate solution and stirred for 30 minutes. The reaction mixture was concentrated and the aqueous layer was extracted with 250ml of ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 20g (95%).

¹H-NMR(CDCl₃)：δ7.288～7.366，(m，5H)，5.100(s，2H)，4.133～4.191(m，1H)，3.146(br s，1H)，2.548(dd，1H)，2.338(t，2H)，2.235(dd，1H)，1.245～2.03022H)，0.925(t，3H)

¹³C-NMR(CDCl₃)：δ213.977，173.595，135.977，128.450，128.313，128.175，128.092，128.076，122.267(t)，97.031(dd)，71.489，66.031，53.076，45.870，43.550，34.153，30.359(t)，29.351(29.305)，28.771，27.893，27.107，26.870，24.748，23.458，22.924(22.893)，22.489，13.804

Example 24

4-Methoxybenzenem-7- [ (2R, 4aR, 5R, 7aR) -2- (1, 1-difluoropentyl) -octahydro-2-hydroxy-6-oxo-cyclopenta [ b ] pyran-5-yl) heptanoic acid methyl ester

4-Methoxybenzyl 7- [ (1R,2R,3R) -2- (4, 4-difluoro-3-keto-octyl) -5-keto-3- (tetrahydrofuran-2-yloxy) cyclopentyl) heptanoate of example 21 (70g, 120mmol) dissolved in 700ml of acetonitrile was added to a 2l three-necked flask, followed by addition of distilled water (70ml) and 3N HCl (7ml) and stirring at room temperature for 1 hour. The reaction mixture was poured into 300ml of saturated aqueous sodium bicarbonate solution and stirred for 30 minutes. The reaction mixture was concentrated and the aqueous layer was extracted with 1L of ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and the solid was filtered off. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient exfoliant. The yield of the title compound was 60g (97%).

¹H-NMR(CDCl₃)：δ7.285(d，2H)，6.883(d，2H)，5.040(s，2H)，4.109～4.198(m，1H)，3.799(br s，3H)，3.171(br s，1H)，2.551(dd，1H)，2.314(t，2H)，2.242(dd，1H)，1.240～2.039(m，22H)，0.934(t，3H)

¹³C-NMR(CDCl₃)：δ213.924，173.644，159.476，129.928，128.126，122.262(t)，113.833，97.010(t)，71.476，65.828，53.166，53.063，45.884，43.536，34.178，30.339(t)，29.336，28.753，27.881，27.105，26.871，24.739，23.457，22.918，22.479，13.820

Example 25

7- [ (2R, 4aR, 5R, 7aR) -2- (1, 1-difluoropentyl) -octahydro-2-hydroxy-6-oxo-cyclopenta [ b ] pyran-5-yl) heptanoic acid, lubiprostone

The method A comprises the following steps: 4-Methoxybenzenese methyl 7- [ (2R, 4aR, 5R, 7aR) -2- (1, 1-difluoro-pentyl) -octahydro-2-hydroxy-6-oxo-cyclopenta [ b ] pyran-5-yl) heptanoate (60g, 118mmol) of example 24 was dissolved in 600ml of ethyl acetate and then 5% palladium on activated carbon was added and maintained under hydrogen for 3 hours. Subsequently, the reaction mixture was filtered through a celite pad. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient solvent to give 40g of oily product (purity. gtoreq.99.0%, determined by HPLC). The oily product was dissolved in isopropyl ether (40m1) and n-pentane (120ml) was added while stirring for 12 hours. The solid was filtered off, washed with n-pentane and dried under vacuum at 40 ℃ to give 31g of white crystalline compound (yield: 68%, purity. gtoreq.99.9%, determined by HPLC).

The method B comprises the following steps: benzyl 7- [ (1R,2R,3R) -3-benzyloxy-2- (4, 4-difluoro-3-keto-octyl) -5-keto-cyclopentyl ] heptanoate of example 22 (2g, 3.5mmol) was dissolved in 25ml of ethyl acetate and then 5% palladium on activated carbon was added, and maintained under hydrogen for 1 hour. Subsequently, the reaction mixture was filtered through a celite pad. The solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent to give 1.2g of the product as an oil. The oily product was dissolved in isopropyl ether (3ml) and n-pentane (10ml) was added while stirring for 12 hours. The solid was filtered off, washed with n-pentane and dried under vacuum at 40 ℃ to give 0.95g of white crystalline compound (yield: 69%, purity. gtoreq.99.9%, determined by HPLC).

¹H-NMR(CDCl₃)：δ4.127～4.199(m，1H)，2.553(dd，1H)，2.323(t，2H)，2.233(dd，1H)，1.296～2.000(m，24H)，0.914(t，3H)

¹³C-NMR(CDCl₃)：δ214.081，179.782，122.296(t)，97.158(t)，71.588，53.137，45.926，43.604，33.911，30.488(t)，29.403，28.765，27.968，27.156，26.928，24.530，23.498，22.966(t)，22.557，13.912。

MS(EI)：m/e 390(M⁺)，372(M⁺-H₂O)，354(M⁺-2 H₂O)

C₂₀H₃₂F₂O₅Analytical calculation of (a): c, 61.52; h, 8.26. Experimental values: c, 61.34; h, 8.28.

Although the present invention has been described with reference to illustrative examples, it is to be understood that any modifications or alterations that may be readily accomplished by those skilled in the art will be within the scope of the disclosure of this specification and the appended claims.