JP2015120693A - Processes for preparation of lubiprostone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide new processes for preparing and purifying lubiprostone.SOLUTION: A process involves 1,4-conjugate addition of a higher order cuprate compound to a protected cyclopentenone intermediate as an important preparation step. Obtained lubiprostone is converted into a guanidine salt derivative that possesses a different melting point and solubility than lubiprostone, and thereby lubiprostone is refined. A novel synthetic intermediate is also present.

Description

  The present invention provides an effective synthetic method for making lubiprostone.

  Rubiprostone, 7-[(1R, 3R, 6R, 7R) -3- (1,1-difluoropentyl) -3-hydroxy-8-oxo-2-oxabicyclo [4.3.0] non-7-yl ] Heptanoic acid is an active pharmaceutical ingredient (API; API) in gastrointestinal drugs used to treat Amitiza® formulations, chronic idiopathic constipation in adults. It is available from Sucampo Pharmaceuticals, Inc. And was approved by the US Food and Drug Administration (FDA) on January 31, 2006. It also received FDA approval on April 29, 2008 to treat irritable bowel syndrome (ISB-C) with constipation in adult women over the age of 18. Amitiza® is also undergoing clinical trials for other gastrointestinal disorders. Rubiprostone is a bicyclic 13,14-dihydro-15-keto-16,16-difluoro-prostaglandin E1 derivative (also known as the so-called 13,14-dihydro-15-keto-prostaglandin derivative). is there. Prostaglandins have a prostanoic acid skeleton which is a C20 fatty acid (FIG. 1).

図１−プロスタグランジンの命名

Figure 1-Prostaglandin naming

The presence of an electron-deficient ketone at the C15 position, combined with the hydroxyl group at the C11 position at a convenient position, yields rubiprostone, which exists mostly in a bicyclic form containing a 6-membered hemiketal ring. This form exists in equilibrium with the monocyclic form (Scheme 1). Taken together, these two forms are referred to as tautomers. In glycochemistry, this type of equilibrium between cyclic and acyclic forms is called ring-chain tautomerization (R-CT) (Non-Patent Document 1; according to Non-Patent Document 1, ring- Chain tautomerization "occurs when proton transfer is accompanied by a change from an open structure to a ring, such as the open and pyran forms of glucose"). In D ₂ O, the ratio of the bicyclic form to the monocyclic form is 6: 1, while in CDCl ₃ it is 96: 4 (Patent Document 1). Despite this tautomerization and the advantage of the bicyclic hemiketal form, rubiprostone is still referred to as a 15-keto-prostaglandin E1 derivative. According to Patent Document 2, the two reported crystalline polymorphs of rubiprostone exist as solid state bicyclic forms.

スキーム１−ルビプロストンの「環−鎖互変異性体」形態

Scheme 1-"Ring-chain tautomer" form of rubiprostone

Related Art An early approach with great versatility in the synthesis of prostaglandins and analogs is described in E. J. et al. Invented in the late 60s by Corey (Non-Patent Document 2), this is probably the most used strategy in the industry. In addition to the currently claimed method, to date, it is the only method disclosed for the synthesis of rubiprostone. This approach is referred to as the “Cory method”. Corey lactone aldehyde (also known as Corey aldehyde) (Non-Patent Document 3), which itself requires many synthetic steps, is the center of the Corey approach, and already has three PGE ₁ stereochemistry in place. It contains all of the target centers (such as those required for rubiprostone), and the ω-side chain and α-side chain are added sequentially by the Horner-Wadsworth-Emmons reaction (or HWE reaction) and the Wittig reaction. (Scheme 2). In the Corey approach, the order of adding α-side chains and ω-side chains can be alternated.

スキーム２−プロスタグランジンを合成する「コーリー法」

Scheme 2-"Cory method" for synthesizing prostaglandins

US Pat. No. 7,355,064 US Patent Application Publication No. 20110056808

http://en.wikipedia.org/wiki/Tautomer J. Am. Chem. Soc., 1969, 91, 5675-5676. Angew. Chem. Int. Ed. Engl., 1991, 30, 455-465.

Prostaglandin Platform Technology of the Invention Our company has previously developed a total synthesis of the prostaglandin analogs travoprost and bimatoprost. These synthetic pathways and their processes were published in 2009 in US Patent Application Publication No. 2009059058 and International Publication No. 2009/141718. The final step in the synthesis of travoprost and bimatoprost is shown in Scheme 3 and is high with cyclopentenone (1) (a branched common intermediate) to give PGE ₂ compounds (3A) or (3B). Centered on the important 1,4-conjugate addition reaction (aka Michael addition) of the next cuprate (formed from compound (2A) or (2B)). Following this, the two PGE ₂ were converted to PGF _2α compounds (4A) or (4B) by stereoselective C9 ketone reduction. This was followed by double TBS deprotection (C11-OTBS and C15-OTBS) to provide the isopropyl ester analog of travoprost or bimatoprost, compound (5). The isopropyl ester was converted to bimatoprost by ester amide exchange.

  For lubiprostone, the subject of the present invention, we utilized a different synthetic route because the structure of the API is quite different from that of bimatoprost and travoprost, but the important intermediate compound (1) is still one of the cuprate compounds 1 , 4-conjugate addition is similarly used. Therefore, the branched intermediate (1) for which we have a production method can still be used for the synthesis of rubiprostone.

スキーム３−我々のプロスタグランジンプラットフォーム技術を用いたトラボプロスト及びビマトプロストの合成における最終工程（米国特許出願公開第２００９０２５９０５８号明細書及び国際公開第２００９／１４１７１８号）

Scheme 3-Final steps in the synthesis of travoprost and bimatoprost using our prostaglandin platform technology (US Patent Application Publication No. 2009059058 and International Publication No. 2009/141718)

Application of prostaglandin platform technology to the synthesis of rubiprostone:
Our preferred synthesis of rubiprostone is shown in Scheme 4. We propose that silyl protecting groups can be selected from a variety of analogs, but TBS is preferred. The α-side chain may have a double bond between C5 and C6, which may be cis- or trans- or a mixture of cis- and trans-, but C5-C6 is saturated. It may be. The C17-C18-C19 bonds may all be C-C single bonds, but may contain one double bond and one single bond. The presence of a double bond between C17 and C18 or between C18 and C19 is only an artifact of the synthesis of II. The stereochemical configuration of C15 may be (R)-or (S)-, or may be a mixture. A benzyl protecting group may be unsubstituted (ie, R ¹⁴ = H) or substituted (ie, R ¹⁴ = 4-MeO, 2,4-DiMeO, etc.). R ¹³ can be any substituent or combination of substituents that allows cuprate III to efficiently transfer its vinyl group to cyclopentenone I but not itself react with cyclopentenone I. R ¹³ is preferably selected from the group of cyano, methyl and thienyl, and combinations of these with lithium counter ions. As far as possible, other organocopper reagents may also be used. After the 1,4-conjugate addition of cuprate III and cyclopentenone I (step 1c), all of the compound IV together with benzyl or substituted benzyl groups using a metal catalyst, preferably Pd, in a hydrogen atmosphere. Remove the double bond (C13, C14, for example, between C5 and C6, between C17 and C18, and everything else between C18 and C19) (step 2). This is followed by oxidation of the C15 alcohol of Compound V to a ketone using any suitable reagent, but preferably one that does not contaminate the product with metal residues (eg, Pfitzner-Moffat type oxidation reagent). 15-ketoprostaglandin VI is a doubly protected form of rubiprostone, which is preferably achieved with the aid of an enzyme to provide compound VII (step 4i ) And then desilylation with acidic conditions or fluoride reagent (step 5i) to provide an isopropyl ester of rubiprostone, or desilylation with acidic conditions or fluoride reagent (step 4ii) and then Converted to rubiprostone by isopropyl ester hydrolysis (step 5ii), preferably achieved with the aid of an enzyme.

R ¹¹ of ester VIII can be alkyl, benzyl, aryl, but methyl and ethyl are preferred. R ⁴ , R ⁵ and R ⁶ may be any of alkyl and aryl, but all are preferably methyl. R ⁷ is H or BnR ¹⁴ . R ¹⁵ can be SnR ⁸ R ⁹ R ¹⁰ , Br, I, ZrCp ₂ Me, but is preferably SnR ⁸ R ⁹ R ¹⁰ . R ⁸ , R ⁹ and R ¹⁰ may be either alkyl or aryl, but all are preferably n-butyl. R ¹³ is absent or Li (CN), Li ₂ (CN) Me, Li ₂ (CN) 2 -thienyl, Li (CH═CHCH (OBnR ¹⁴ ) CF ₂ CH _n CH _m CH _o CH ₃ ) (C17 N, m and o are 1 or 2 such that from C19 to C19 are fully saturated or C17 to C19 contain one single bond and one double or triple bond), _{li 2 (CN) (CH =} CHCH (OBnR 14) CF 2 CH n CH m CH o CH 3) (C17 from until completely saturated and which may or C17 C19 until C19 is one one single bond and a two N, m and o are 1 or 2 so as to contain a heavy or triple bond), but preferably Li ₂ (CN) Me or Li ₂ (CN) 2-thienyl.

  An important aspect of the present invention that has not been reported so far is that as an important step of forming the prostaglandin skeleton of rubiprostone from cyclopentenone I and higher order cuprate III in one single step, 1,4- Use of conjugate addition is included. This is followed by the efficient use of hydrogenation / hydrocracking to remove all IV double bonds, which are an artifact of the synthesis of IV, while simultaneously removing the C15-O protecting group and providing V. Another important aspect of the synthesis is the use of enzymes to remove ester protecting groups. Hydrolysis of isopropyl ester under acidic or basic aqueous conditions causes degradation of the sensitive 15-keto-PGE structure and can also remove the silyl protecting group, so it is not orthogonal, thereby synthesizing us This is preferred because it does not provide any control. The last two steps are deprotection steps, but can be performed in either order.

  Of course, other ester analogs (eg, methyl, ethyl, propyl, etc.) may be used following the synthetic route of the present invention in the synthesis of rubiprostone, but isopropyl is preferred.

スキーム４−ルビプロストンの合成の好適な方法の概要（番号は、ルビプロストンで見られる原子の番号を反映して示す）

Scheme 4-Overview of preferred method of synthesis of rubiprostone (numbers reflect the number of atoms found in rubiprostone)

  Thus, the present invention includes a new synthetic route to rubiprostone (Scheme 5), which includes the higher order cuprate compound Cu-IM7 (prepared in situ from IM7) to the protected cyclopentenone (1). Of 1,4-conjugate addition as an important step. We also provided a synthetic route to IM7 (Scheme 7) and IM7b (Scheme 8) (and 4-methoxybenzyl derivatives IM7i and IM7bi) which are starting materials for the ω-side chain of rubiprostone. Unlike all the prior art syntheses of rubiprostone we know, we utilized a silicon-based protecting group for the protection of alcohols that eventually become C11-O in rubiprostone. All other prior art methods disclosed to the best of our knowledge disclose the use of carbon-based protecting groups such as THP. Also, unlike all other prior art methods we know, we prepared rubiprostone by a 1,4-conjugate addition approach that differs significantly from the Corey method used in all other prior art methods. This also defines our approach away from all other methods.

  Hereinafter, the synthesis route will be discussed in detail.

1) Synthesis of rubiprostone (Scheme 5):
Step 1: The first step involves a 1,4-conjugate addition of higher order cuprate Cu-IM7 (step 1c) with an important branched intermediate (1) to provide the PGE ₂ product (7). . The higher order cuprate Cu-IM7 in this step is a stepwise reaction of MeLi and IM7 (step 1a) to form the vinyllithium derivative Li-IM7, followed by the in situ prepared cuprate salt (MeCu ( CN) Li) and prepared in situ by conversion to higher order cuprate Cu-IM7 (step 1b) (see also scheme 6). THF was preferred as the main solvent for this reaction step, and the reaction was performed at low temperature (preferably less than −30 ° C.).

  In addition to the benzyl protecting group used for protected C15-OH (ie, IM7 C3-OH), p-methoxybenzyl (also known as 4-methoxybenzyl) is also tested as a protecting group. Therefore, Step 1 also uses a p-methoxybenzyl derivative to provide the product p-methoxybenzyl ether (7i) with compound (1) and higher cuprate Cu-IM7i (p-methoxybenzyl IM7 analog). , Prepared from IM7i) by 1,4-conjugate addition.

  Step 2: We performed a total hydrogenation / hydrocracking using a palladium catalyst supported on carbon in an organic solvent in a hydrogen atmosphere and performed all three double bonds (C5-C6, C13-C14 and C17-18) and the benzyl protecting group (or p-methoxybenzyl group when compound (7i) was used) were provided at the same time to provide compound (8). Although EtOAc was the preferred solvent, other solvents including EtOH could be used. An acid catalyst (p-TsOH etc.) could also be used for the reaction.

Step 3: C15-OH was oxidized by the swarnidation method (ie, (COCl) _{2 with} DMSO) to provide the diketone (9). Other oxidizing agents including pyridine sulfur trioxide complex / DMSO can also be used.

  Step 4i: Various catalysts capable of catalyzing ester hydrolysis (including lipase PS IM, lipase PS SD, PPL, PS IM) hydrolyze the isopropyl ester of compound (9) under various reaction conditions. Has been found to provide its carboxylic acid form (10). A wide range of organic solvents including acetone, glycol, glycerol, DMSO could be used. Typically, the hydrolysis reaction was performed at elevated temperature (eg, between 30-60 ° C.) and the appropriate pH range. When acetone as an organic solvent was used in combination with an aqueous buffer at high temperature, commercially available lipase PS SD was suitable.

Step 5i: Rubiprostone is a TBS deprotection of C11-OTBS of compound (10) using a mineral or organic acid such as H ₂ SO ₄ , HCl, TFA or a fluoride reagent containing TBAF and hydrous HF in an organic solvent. Prepared by H ₂ SO _{4 in} MeCN is preferred.

  Alternatively, the last two steps (ie step 4i and step 5i) consist of the TBS deprotection of step 4ii (using acid or fluoride reagent) followed by the ester hydrolysis of step 5ii (in aqueous buffer / organic solvent). Can also be carried out in the reverse order).

  Rubiprostone can be converted to a salt derivative by reaction with a base containing a nitrogen-containing base such as guanidine. These salts can have different melting points and solubilities compared to rubiprostone, thereby providing access to alternative methods by which rubiprostone can be purified. We provide a simple method of forming the guanidine salt of rubiprostone.

スキーム５−ルビプロストンの合成

Scheme 5-Synthesis of rubiprostone

2) Synthesis of ω-side chain:
Lubiprostone is for forming the PGE ₂ compound is prepared by the 1,4 conjugate addition of the compound (1) higher order cuprate (Cu-IM7, Cu-IM7b , Cu-IM7i or Cu-IM7bi). Higher order cuprate Cu-IM7 (or Cu-IM7b, Cu-IM7i or Cu-IM7bi) is prepared from trans-vinylstannane IM7 (or IM7i, IM7b or IM7bi) as shown in Scheme 6. By using the commercially available low order cuprate salt 2-thienyl (cyano) copper lithium in step 1b instead of methyl (cyano) copper lithium (MeCu (CN) Li) to provide Th-Cu-IM7, The methyl dummy ligand can be substituted with a 2-thienyl group.

スキーム６−化合物（１）との１，４−共役付加に必要とされる必須の高次クプラートの合成

Scheme 6—Synthesis of Essential Higher Order Cuprate Required for 1,4-Conjugate Addition with Compound (1)

We prepared the requisite trans-vinyl stannane IM7 (or IM7i) by the method as shown in Scheme 7. Commercially available inexpensive SM1 was converted in situ to its organozinc bromide derivative and reacted with commercially available inexpensive butanal to provide alcohol IM1. This was preferably done in THF, and it could be beneficial to add a Lewis acid. Removal of C3-oxygen was achieved by its conversion to the triflate IM2, followed by elimination facilitated by a base containing DBU to provide IM3. The presence of double bonds in IM3 is not critical at all, and rubiprostone can be synthesized from either IM3 or IM3b (see Scheme 8). After its synthesis, IM3 was converted to acylacetylene IM4, which was reduced and desilylated in one pot to provide propargyl alcohol IM5. Therefore, IM5 is treated with Bu ₃ SnH in the presence of the radical initiator AIBN to provide De-Bn-IM7, then basic conditions (eg NaH or t-BuONa, the former being preferred O-protection was performed using benzyl bromide to provide IM7. Alternatively, the C3-OH of IM5 could be protected, then the product IM6 was stannylated to give IM7.

スキーム７−高次クプラートＣｕ−ＩＭ７に必要とされるＩＭ７の合成

Scheme 7-Synthesis of IM7 required for higher order cuprate Cu-IM7

  As noted above, the IM3 analog 2,2-difluorohexanoic acid ethyl (IM3b) is commercially available. IM3b was converted to IM7b by the same synthetic sequence as described in Scheme 7 (Scheme 8).

スキーム８−高次クプラートＣｕ−ＩＭ７ｂに必要とされるＩＭ７ｂの合成

Scheme 8-Synthesis of IM7b required for higher order cuprate Cu-IM7b

Example 1
Step 1: Synthesis of IM1 (ethyl 2,2-difluoro-3-hydroxyhexanoate) Zinc (108 g, 1.66 mol), n-butanol (100 g, 1.39 mol), CeCl ₃ mechanically stirred at about 25 ° C. To a mixture of 7H ₂ O (10.14 g, 0.027 mol) and anhydrous THF (1.3 L) under N ₂ , ethyl 2-bromo-2,2-difluoroacetate (SM1, 33.8 g, 0.167 mol) ) Was added. The mixture was stirred at about 25 ° C. until the reaction started, then SM1 (304 g, 1.50 mol) was added dropwise at 35 ° C. without external heating. After the addition was complete, the mixture was stirred at 20-35 ° C. until n-butanol was less than 2.0%. The reaction mixture was then cooled to about 5 ° C., saturated aqueous NH ₄ Cl (800 mL) was added slowly at about 5 ° C., and then adjusted to pH 3.0 using 6N HCl. The mixture was stirred for 15 minutes and then filtered through a celite plug; the filter cake was washed once with MTBE (1 L). The combined filtrate was then separated and the aqueous layer was extracted once with MTBE (1 L). The combined organic layers were washed once with saturated aqueous NaHCO ₃ (1 L), once with saturated aqueous NH ₄ Cl (1 L), then concentrated at <50 ° C. under reduced pressure and 281 g of GC purity 80%. Crude IM1 was given. The crude IM1 was purified by vacuum distillation to give 160 g of IM1 with a GC purity of 98% and a total GC yield of 58%.
¹ H NMR (300MHz, CDCl ₃ ): δ 4.36 (q, J = 7.1 Hz, 2H), 4.10-3.98 (m, 1H), 1.68-1.58 (m, 2H), 1.57 -1.40 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H)
m / z (GC-MS): 197 ([MH] ⁺ , 1), 124 (75), 96 (100), 73 (45), 55 (80)

Example 2
Step 2: Synthesis of IM2 (ethyl 2,2-difluoro-3- (trifluoromethylsulfonyloxy) hexanoate) IM1 (3 g, 0.015 mol) in anhydrous DCM (6 mL) mechanically stirred at 0-5 ° C. And a solution of Tf ₂ O (4.53 g, 0.016 mol) in anhydrous DCM (3 mL) dropwise into a solution of pyridine (1.42 g, 0.018 mol) at 0-15 ° C. under N ₂ . Was added. The mixture was stirred at 5-15 ° C. until IM1 was less than 2.0%. Water (9 mL) was then added and the resulting mixture was separated. The aqueous layer was extracted once with DCM (9 mL) and the combined organic layers were washed once with 5% aqueous HCl (9 mL), once with saturated aqueous NaHCO ₃ (9 mL) and once with brine (9 mL). And then concentrated under reduced pressure at <45 ° C. to give 4.2 g of crude IM2 with a GC purity of 96%.
¹ H NMR (300MHz, CDCl ₃ ): ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.21 (m, 1H), 4.40 (q, J = 7.2 Hz, 2H), 2.00-1.74 (m, 2H), 1.70 -1.43 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H)
m / z (GC-MS): 329 ([MH] ⁺ , 1), 151 (20), 124 (15), 106 (70), 77 (100), 69 (45), 55 (55)

Example 3
Step 3: Synthesis of IM3 (ethyl 2,2-difluorohex-3-enoate) In a mechanically stirred flask, IM2 (300 g, 0.91 mol) and DBU (165 g, 1.08 mol) in anhydrous MTBE (900 mL). Was added and the mixture was heated to reflux with stirring until IM2 was less than 3.0%. The reaction mixture was then cooled to 0-10 ° C., after which 5% aqueous HCl (900 mL) was added. The resulting solution was separated and the aqueous layer was extracted once with MTBE (900 mL). The combined organic layers were washed once with saturated aqueous NaHCO ₃ (900 mL), once with brine (900 mL), dried over anhydrous MgSO ₄ and then concentrated under reduced pressure at <45 ° C. to give 167 g of crude IM3 was given. The crude IM3 was purified by vacuum distillation to give 125 g of IM3 with a GC purity of 85% and a GC yield of 66% based on IM1.
¹ H NMR (300MHz, CDCl ₃ ): δ 6.33 (dtt, J = 11.5, 6.2, 2.6 Hz, 1H), 5.75-5.58 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.24- 2.11 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.4 Hz, 3H)
m / z (GC-MS): 179 ([MH] ⁺ , 4), 106 (65), 77 (100), 55 (20)

Example 4
Step 4: Synthesis of IM4 (4,4-difluoro-1- (trimethylsilyl) oct-5-en-1-in-3-one) TMS- in anhydrous THF (880 mL) mechanically stirred at 0-10 ° C. A solution of n-BuLi (2.5 mol / L, 748 mL, 1.87 mol) was added to a solution of acetylide (182 g, 1.85 mol) dropwise at 0-10 ° C. under N ₂ . The reaction mixture was stirred at this temperature for 1 hour. A mechanically stirred flask was charged with IM3 (220 g, 1.23 mol, 1.0 eq., GC purity 92%) and BF ₃ / Et ₂ O (264 g, 1.86 mol) in anhydrous THF (220 mL) under N ₂ . added. The solution was cooled to −70 to −78 ° C., and then the TMS-acetylene-lithium solution was added at −60 to −78 ° C. over 2 hours. The reaction solution was stirred at −70 to −78 ° C. until IM3 disappeared. NH ₄ Cl saturated aqueous solution (1.1 L) was slowly added into the reaction, and the temperature was warmed to 0-10 ° C. The mixture was then extracted once with EtOAc (550 mL) and then separated; the aqueous layer was extracted once with EtOAc (550 mL). The combined organic layers were washed once with water (660 mL) and once with brine (660 mL) and then concentrated under reduced pressure at <55 ° C. to give 297 g of crude IM4 with a GC purity of 87%.
¹ H NMR (300MHz, CDCl ₃ ): ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.37 (dtt, J = 11.3, 6.3, 2.5 Hz, 1H), 5.69-5.52 (m, 1H), 2.26-2.13 ( m, 2H), 1.06 (t, J = 7.4 Hz, 3H), 0.28 (s, 9H)
m / z (GC-MS): 231 ([MH] ⁺ , 1), 125 (100), 97 (35), 73 (30)

Example 5
Step 5: Synthesis of IM5 (4,4-difluorooct-5-en-1-in-3-ol) Solution of IM4 (321 g, 1.4 mol) in MeOH (1.5 L) at 0-5 ° C. To was slowly added solid NaBH ₄ (19.6 g, 0.7 mol). The reaction solution was stirred at this temperature until IM4 was consumed. Solid NaOMe (37.7 g, 0.7 mol) was then added and the reaction solution was stirred at this temperature until TMS-IM5 was consumed. NH ₄ Cl saturated aqueous solution (1 L) and H ₂ O (1 L) were added, then the mixture was adjusted to pH 5-6 with 6M HCl, after which the mixture was added 3 times with MTBE (600 mL each). Extracted once. The combined organic layers were washed once with water (600 mL) and once with brine (600 mL) and then concentrated under reduced pressure at <45 ° C. to give 224 g of crude IM5 with a GC purity of 87%.
¹ H NMR (300MHz, CDCl ₃ ): δ 6.32 (dtd, J = 10.8, 6.1, 2.3 Hz, 1H), 5.78-5.59 (m, 1H), 4.57-4.46 (m, 1H), 2.55 (d, J = 2.2 Hz, 1H), 2.26-2.12 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H)
m / z (GC-MS): 159 ([MH] ⁺ , 1), 105 (5), 77 (100), 55 (30)

Example 6
Step 6: Synthesis of De-Bn-IM7 ((1E) -4,4-difluoro-1- (tributylstannyl) octa-1,5-dien-3-ol) IM5 in toluene (550 mL) (110 g, To a hot (70 ° C.) solution of 0.68 mol) with stirring, Bu ₃ SnH (219 g, 0.75 mol) and AIBN (12.4 g, 0.075 mol) are added and the mixture until IM5 is consumed Was stirred at 80-85 ° C. The reaction mixture was evaporated at <55 ° C. to give 338 g of crude De-Bn-IM7. Purify the crude De-Bn-IM7 by column chromatography to give 81.5 g of De-Bn-IM7 with a GC purity of 91%, and 111.5 g of a mixture of cis-De-Bn-IM7 and De-Bn-IM7. It was.
¹ H NMR (300MHz, CDCl ₃ ): δ 6.48-6.40 (m, 1H), 6.27-6.13 (m, 1H), 6.01 (dd, J = 19.3, 5.1 Hz, 1H), 5.55 (dtt, J = 15.4 , 11.9, 1.7 Hz, 1H), 4.34-4.22 (m, 1H), 2.20-2.11 (m, 2H), 1.55-1.43 (m, 6H), 1.30 (dq, J = 14.0, 7.1 Hz, 6H), 1.03 (t, J = 7.4 Hz, 3H), 0.90 (dd, J = 14.5, 7.3 Hz, 15H)
m / z (ES-API, Neg): 451, 495 (M + HCOO -)

Example 7
Step 7: Synthesis of IM7 (((1E, 5E) -3- (benzyloxy) -4,4-difluoroocta-1,5-dienyl) tributylstannane) NaH (4 in mechanically stirred DMF (170 mL) To a mixture of De-Bn-IM7 (42 g, 93.1 mmol) in DMF (20 mL) at −10 to 0 ° C. and the reaction mixture to this temperature. The solution of BnBr (16.7 g, 97.7 mmol) in DMF (20 mL) is added dropwise into the reaction mixture at −10 to 0 ° C. until the De-Bn-IM7 is consumed. added. Water (210 mL) was added and the mixture was extracted twice with MTBE (210 mL each). The combined organic layers were washed once with saturated aqueous NH ₄ Cl (210 mL), once with water (210 mL), once with brine (210 mL), then concentrated under reduced pressure at <45 ° C. and HPLC This gave 52.3 g of crude IM7 with a purity of 91.1%.
¹ H NMR (300MHz, CDCl ₃ ): δ 7.39-7.26 (m, 5H), 6.38 (d, J = 19.2 Hz, 1H), 6.19-6.09 (m, 1H), 5.88 (dd, J = 19.2, 6.8 Hz, 1H), 5.60 (dtt, J = 15.4, 11.9, 1.7 Hz, 1H), 4.69 (d, J = 12.2 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 3.94-3.87 (m , 1H), 2.20-2.06 (m, 2H), 1.57-1.43 (m, 6H), 1.32 (dt, J = 15.0, 7.4 Hz, 6H), 1.02 (t, J = 7.4 Hz, 3H), 0.91 ( q, J = 7.5 Hz, 15H)
m / z (EI): 581 ([M + K ⁺ ], 100), 565 ([M + Na ⁺ ], 60)

Example 8
Step 8: Synthesis of IM7i (((1E, 5E) -3- (benzyloxy) -4,4-difluoroocta-1,5-dienyl) tributylstannane) NaH (0 in mechanically stirred DMF (20 mL)) To a mixture of .49 g, 60%, 0.012 mol) was added a solution of De-Bn-IM7 (5 g, 0.011 mol) in DMF (2.5 mL) at −10 to 0 ° C., and the reaction mixture was added to the reaction mixture. Stir at temperature for 1 hour and in the reaction mixture at −10 to 0 ° C. in the DMF (2.5 mL) until the De-Bn-IM7 is consumed, 1- (bromomethyl) -4-methoxybenzene (2. 34 g, 0.0116 mol) solution was added dropwise. Water (25 mL) was added and the mixture was extracted twice with MTBE (25 mL each). The combined organic layers were washed once with saturated aqueous NH ₄ Cl (25 mL), once with water (25 mL), once with brine (25 mL), then concentrated under reduced pressure at <45 ° C., 6 .3 g of crude IM7i was given. The crude IM7i was purified by column chromatography to give 4.2 g of IM7i with GC purity of 92% and HPLC yield of 64%.
¹ H NMR (300MHz, CDCl ₃ ): δ 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.42-6.31 (m, 1H), 6.13 (d, J = 15.8 Hz, 1H), 5.87 (dd, J = 19.2, 6.7 Hz, 1H), 5.58 (dd, J = 26.5, 13.2 Hz, 1H), 4.62 (d, J = 11.8 Hz, 1H), 4.44 (d, J = 11.8 Hz, 1H), 3.94-3.87 (m, 1H), 2.20-2.06 (m, 2H), 1.57-1.43 (m, 6H), 1.32 (dt, J = 15.0, 7.4 Hz, 6H), 1.02 (t, J = 7.4 Hz, 3H), 0.91 (q, J = 7.5 Hz, 15H)
m / z (ES API, Pos): 611 ([M + K ⁺ ], 100), 595 ([M + Na ⁺ ], 70)

Example 9
Step 9: Synthesis of IM6 ((E)-((4,4-difluorooct-5-en-1-in-3-yloxy) methyl) benzene) IM5 (100 g, GC in mechanically stirred THF (300 mL) To a mixture of 76% purity, 0.62 mol) and t-BuOK (71.4 g, 0.74 mol), a solution of BnBr (116 g, 0.68 mol) in THF (200 mL) was added at 60-70 ° C., The reaction mixture was stirred at this temperature for 1 hour until IM5 was less than 5%. The mixture was cooled to 15-30 ° C., water (1 L) and MTBE (1 L) were added, the mixture was stirred for 15 minutes, and the aqueous layer was extracted once with MTBE (500 mL). The combined organic layers were washed once with saturated aqueous NH ₄ Cl (500 mL) and once with brine (500 mL), then concentrated under reduced pressure at <45 ° C. and 155 g of crude IM6 at 61% HPLC purity. Gave. The crude IM6 was purified by column chromatography to give 86 g of IM6 with a GC purity of 86% and a GC yield of 62%.
¹ H NMR (300MHz, CDCl ₃ ): δ 7.37-7.31 (m, 5H), 6.35-6.22 (m, 1H), 5.78-5.61 (m, 1H), 4.86 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.29 (dt, J = 8.0, 2.2 Hz, 1H), 2.55 (d, J = 8.0, 2.1 Hz, 1H), 2.22-2.09 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H)

Example 10
Step 10: Synthesis of IM7 To a hot (80 ° C.) solution of IM6 (69 g, 86%, 0.28 mol) in toluene (340 mL), Bu ₃ SnH (88 g, 0.30 mol) and AIBN (5.1 g, 0 0.03 mol) was added under stirring. The mixture was stirred at 80-85 ° C. until IM6 was consumed. The reaction mixture was evaporated at <55 ° C. to give 150 g of crude IM7. The crude IM7 was purified by column chromatography to give 75 g of IM7 with a GC purity of 61.2% and a GC yield of 65%.

Step 1a: Synthesis of Compound (7) ((Z) -7-((1R, 2R, 3R) -2-((1E, 5E) -3- (benzyloxy) -4,4-difluoroocta-1, 5-dienyl) -3- (tert-butyldimethyl-silyloxy) -5-oxocyclopentyl) hept-5-enoic acid isopropyl)
Example 11
To a mixture of CuCN (26.7 g, 0.3 mol) in THF (375 mL) at −10 to 0 ° C., a solution of MeLi in diethoxymethane (91 mL, 3 M, 0.27 mol) was added dropwise under N _2. added. The reaction mixture was stirred at this temperature for 0.5 hour. To a solution of IM7 (147 g, HPLC purity 90%, 0.27 mol) in THF (750 mL) at −60 to −70 ° C. while dropping dropwise under N ₂ , a solution of MeLi in diethoxymethane (91 mL, 3M, 0 .27 mol) was added. The reaction mixture was stirred at this temperature until IM7 was consumed. During the reaction, the prepared MeCu (CN) Li solution was further added dropwise at −40 to −50 ° C. over 30 minutes. Next, a solution of compound (1) (82.7 g, 0.22 mol) in THF (375 mL) was added dropwise to the previous reaction solution at −50 to −60 ° C. The reaction mixture was stirred at this temperature until the reaction was complete. NH ₄ Cl saturated aqueous solution (750 mL) was added at this temperature, then the resulting mixture was warmed to room temperature, filtered, and the filter cake was washed once with MTBE (750 mL). The filtrate was separated and the aqueous layer was extracted once with MTBE (375 mL). The combined organic layers were washed once with brine (750 mL) and then concentrated under reduced pressure at <55 ° C. to give 228 g of crude compound (7), which was purified by column chromatography, HPLC purity 90 Gave 107 g of compound (7) in a yield of 70% based on% and compound (1).

Example 12
To a solution of IM7 (5 g, 9.2 mmol) in THF (30 mL) at −60 to −70 ° C. while dropping dropwise under N ₂ , a solution of MeLi in diethoxymethane (3.1 mL, 3 M, 9.3 mmol) Was added. The reaction mixture was stirred at this temperature until IM7 was consumed. Lithium 2-thienyl cyanocuprate (37 mL, 0.25 M, 9.25 mmol) was added dropwise under N ₂ . The reaction mixture was stirred at this temperature for 1 hour. Next, a solution of compound (1) (2.8 g, 7.4 mmol) in THF (20 mL) was added dropwise to the previous reaction solution at −50 to −60 ° C. The reaction mixture was stirred at this temperature until the reaction was complete. A saturated aqueous NH ₄ Cl solution (15 mL) was added at this temperature, then the resulting mixture was warmed to room temperature, filtered, and the filter cake was washed once with EtOAc (25 mL). The filtrate was separated and the aqueous layer was extracted once with EtOAc (25 mL). The combined organic layers were washed once with brine (25 mL) and then concentrated under reduced pressure at <55 ° C. with an HPLC purity of 29.5% and an HPLC yield of 51.8% based on compound (1). 8.2 g of crude compound (7) was obtained.
¹ H NMR (300MHz, CDCl ₃ ): δ 7.39-7.27 (m, 5H), 6.24-6.10 (m, 1H), 5.81-5.69 (m, 1H), 5.68-5.50 (m, 2H), 5.49-5.27 (m, 2H), 4.99 (dt, J = 12.5, 6.3 Hz, 1H), 4.68 (dd, J = 12.0, 3.0 Hz, 1H), 4.52 (dd, J = 12.0, 5.9 Hz, 1H), 4.14- 4.04 (m, 1H), 4.04 -3.92 (m, 1H), 2.74-2.66 (m, 1H), 2.65-2.51 (m, 2H), 2.49-2.28 (m, 2H, H8), 2.28-1.96 (m , 5H), 1.75-1.58 (m, 2H), 1.30-1.23 (m, 2H), 1.21 (d, J = 6.3 Hz, 6H), 1.03 (t, J = 7.4 Hz, 3H), 0.88 (s, 9H), 0.05 (dd, J = 5.9, 3.4 Hz, 6H)
m / z (API-ES, Pos): 655 ([M + Na ⁺ ], 100)

Example 13
Step 1b: Synthesis of Compound (7i) ((Z) -7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2-((1E, 5E) -4,4-difluoro -3- (4-methoxybenzyloxy) octa-1,5-dienyl) -5-oxocyclopentyl) hept-5-enoic acid isopropyl)
To a mixture of CuCN (0.77 g, 8.5 mmol) in THF (10 mL) at −10 to 0 ° C. while dropping dropwise under N ₂ , a solution of MeLi in diethoxymethane (2.6 mL, 3 M, 7.8 mmol). ) Was added. The reaction mixture was stirred at this temperature for 0.5 hour. To a solution of IM7i (4.1 g, HPLC purity 92%, 7.8 mmol) in THF (20 mL) at −60 to −70 ° C. dropwise under N ₂ , a solution of MeLi in diethoxymethane (2.6 mL). 3M, 7.8 mmol). The reaction mixture was stirred at this temperature until IM7i was consumed. During the reaction, the prepared MeCu (CN) Li solution was further added dropwise at −40 to −50 ° C. over 0.5 hours. Next, a solution of compound (1) (2.37 g, 6.2 mmol) in THF (10 mL) was added dropwise to the previous reaction solution at −50 to −60 ° C. The reaction mixture was stirred at this temperature until the reaction was complete. A saturated aqueous NH ₄ Cl solution (20 mL) was added at this temperature, then the resulting mixture was warmed to room temperature, filtered, and the filter cake was washed once with MTBE (20 mL). The filtrate was separated and the aqueous layer was extracted once with MTBE (10 mL). The combined organic layers were washed once with brine (20 mL) and then concentrated under reduced pressure at <55 ° C. to give 6.8 g of crude compound (7i), which was purified by column chromatography, HPLC 2.3 g of compound (7i) was obtained with a purity of 88.6% and an HPLC yield of 51% based on compound (1).
¹ H NMR (300MHz, CDCl ₃ ): δ 7.26-7.20 (m, 2H), 6.91-6.83 (m, 2H), 6.25-6.08 (m, 1H), 5.72 (ddd, J = 17.3, 12.8, 4.8 Hz , 1H), 5.65-5.50 (m, 2H), 5.49-5.28 (m, 2H, H5), 4.99 (dt, J = 12.5, 6.3 Hz, 1H), 4.62 (dd, J = 11.6, 2.3 Hz, 1H ), 4.45 (dt, J = 11.6, 5.6 Hz, 1H), 4.17-4.02 (m, 1H), 4.02-3.89 (m, 1H), 3.81 (s, 3H), 2.74-2.50 (m, 2H), 2.49-1.96 (m, 9H), 1.73-1.59 (m, 2H), 1.28 (dd, J = 9.6, 4.4 Hz, 2H), 1.21 (d, J = 6.3 Hz, 6H), 1.02 (t, J = 7.4 Hz, 3H), 0.88 (s, 9H), 0.05 (dd, J = 6.0, 3.3 Hz, 6H).
m / z (API-ES, Pos): 680 ([M + NH ₄ ] ⁺ , 100), 664 (M ⁺ , 10)

Step 2: Synthesis of Compound (8) (7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (4,4-difluoro-3-hydroxyoctyl) -5-oxo Cyclopentyl) isopropyl heptanoate)
Example 14
Prepared previous compound (7) (57 g, HPLC purity 91%, 0.90 mol), 10% Pd / C (5.7 g, 53% H ₂ O) and EtOAc (570 mL) under 0 ₂ under 0. The reaction was stirred at 4 MPa at 60 ° C. until compound (7) was consumed. The reaction mixture was then filtered through a celite plug, the filter cake was washed once with EtOAc (285 mL), and the filtrate was then concentrated under reduced pressure at <55 ° C., yielding 54 g of compound (8). The residue was purified by column chromatography (EtOAc: n-heptane = 1: 10) and 47 g of compound (8) was isolated in 96% crude yield.

Example 15
Prepared previous compound (7i) (2.3 g, HPLC purity 89%, 3.5 mmol), 10% Pd / C (0.23 g, 40% H ₂ O) and EtOAc (23 mL) under H _2. The reaction was stirred at 0.4 MPa and heated to 60 ° C. until the compound (7i) was consumed. The reaction mixture was then filtered through a celite plug, the filter cake was washed once with EtOAc (12 mL), and the filtrate was then concentrated under reduced pressure at <55 ° C. to give 2.0 g of compound (8). .
¹ H NMR (300MHz, CDCl ₃ ): δ 5.07-4.91 (m, 1H), 4.14-4.00 (m, 1H), 3.78-3.58 (m, 1H), 2.65-2.54 (m, 1H), 2.33 (dd , J = 6.3, 30.2 Hz, 1H), 2.25 (t, J = 7.5 Hz, 3H), 2.17 (dd, J = 6.7, 5.3 Hz, 1H), 2.02-1.71 (m, 7H), 1.67-1.25 ( m, 14H), 1.22 (d, J = 6.3, 6H), 0.93 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 1.5 Hz, 9H), 0.07 (dd, J = 9.3, 2.6 Hz , 6H)
m / z (API-ES, Pos): 549 (M + H ⁺ , 100)

Example 16
Step 3: Synthesis of Compound (9) (7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (4,4-difluoro-3-oxooctyl) -5-oxo Cyclopentyl) isopropyl heptanoate)
A solution of oxalyl chloride (1.27 g, 10.0 mmol) in DCM (20 mL) was cooled to −60 to −70 ° C. while DMSO (1.56 g, 20.0 mmol) in DCM (5 mL) was added dropwise. In addition, the solution was stirred for 30 minutes. A solution of compound (8) (5.0 g, 9.1 mmol) in DCM (10 mL) was added dropwise and the mixture was stirred at −60 to −70 ° C. for 1 hour. Et ₃ N (3.04 g, 30.0 mol) was added dropwise to the mixture and the reaction was stirred at this temperature until the reaction was complete. The mixture was warmed to 0 ° C., water (50 mL) was added to the solution, the mixture was stirred for 5 minutes and then separated. The aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed once with saturated NH ₄ Cl (50 mL), once with water (50 mL) and then concentrated under reduced pressure at <50 ° C. with HPLC purity of 87% and HPLC yield of 91%. 4.57 g of compound (9) was given.
¹ H NMR (300MHz, CDCl ₃ ): δ 5.09-4.91 (m, 1H), 4.03 (q, J = 6.7, 1H), 3.00-2.73 (m, 2H), 2.60 (ddd, J = 18.1, 6.6, 1.1 Hz, 1H), 2.25 (t, J = 7.5, 2H), 2.20 (d, J = 7.2 Hz, 1H), 2.14 (d, J = 7.2 Hz, 1H), 2.10-1.25 (m, 21H), 1.22 (d, J = 6.3 Hz, 6H), 0.92 (t, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.07 (d, J = 8.6, 6H)
m / z (EI): 547 (M + H ⁺ , 100), 569 (M + Na ⁺ , 45)

Example 17
Step 4a: Synthesis of Compound (10) (7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (4,4-difluoro-3-oxooctyl) -5-oxo Cyclopentyl) heptanoic acid)
Compound (9) (5.0 g, 9.14 mmol) in acetone (15 mL) and pH 7.0 buffer (0.5% NaH ₂ PO ₄ , pH adjusted to 7.0 with 1N NaOH; 35 mL). To the solution was added lipase PS SD (0.5 g) and stirred at 50 ° C. until most of compound (9) was consumed. The reaction was filtered through a silica gel plug, washed with MTBE (100 mL), and the filtrate. Was washed twice with water (50 mL × 2) and then concentrated under reduced pressure at <40 ° C. to give 4.78 g of crude compound (10).
¹ H NMR (300MHz, CDCl ₃ ): δ: 4.03 (q, J = 6.7 Hz, 1H), 3.00-2.72 (m, 2H), 2.66-2.55 (dd, J = 12.3 Hz, 7.5 Hz, 1H), 2.34 (t, J = 7.5, 2H), 2.17 (dd, J = 18.1Hz, 7.3Hz, 1H), 2.08-1.17 (m, 22H), 0.92 (t, J = 6.9 Hz, 3H), 0.89 (s , 9H), 0.07 (d, J = 8.6, 6H)
m / z (ES-API, Neg): 503 ([MH] ^- , 35), 371 (100)

Example 18
Step 4b: Synthesis of iPr-rubiprostone 7-((2R, 4aR, 5R, 7aR) -2- (1,1-difluoropentyl) -2-hydroxy-6-oxo-octahydrocyclopenta [b] pyran-5 -Yl) Isopropyl heptanoate To a solution of compound (9) (1.0 g, 1.8 mmol) in MeCN (10 mL) was added TFA (1.0 g, 8.8 mmol) and the mixture was at 15-30 ° C. After stirring for 16 hours, TLC analysis showed that compound (9) was less than 20%. Then water (10 mL) and MTBE (10 mL) were added and stirred for 5 minutes, then separated. The aqueous layer was extracted once with MTBE (10 mL). The combined organic layers were washed twice with water (10 mL × 2), once with a saturated aqueous NaHCO ₃ solution (10 mL), then concentrated under reduced pressure at <50 ° C. to give 0.85 g of crude iPr-rubiprostone. Gave.

Example 19
Step 5a: Synthesis of rubiprostone via compound (10) (7-((2R, 4aR, 5R, 7aR) -2- (1,1-difluoropentyl) -2-hydroxy-6-oxo-octahydrocyclopenta- [b] pyran-5-yl) heptanoic acid)
To a solution of compound (10) (3.6 g, 7.14 mmol) in MeCN (54 mL) was added H ₂ SO ₄ (2 mol / L, 3.57 mL, 7.14 mmol) and compound (10) was consumed. The mixture was stirred at 15 ° C. ± 5 ° C. until Water (54 mL) was added and extracted twice with MTBE (36 mL × 2). The combined organic layers were washed once with saturated aqueous NaHCO ₃ (36 mL), once with water (36 mL), dried over anhydrous MgSO ₄ and then concentrated under reduced pressure at <40 ° C., HPLC purity 65% Gave 2.58 g of crude product which was purified by column chromatography to give 1.3 g of rubiprostone with HPLC purity 80%. Rubiprostone (0.5 g, HPLC purity 80%) was dissolved in 20-30 ° C. MTBE (0.5 mL) and then n-heptane (2 mL) was cooled to 0-10 ° C. with vigorous stirring for 2 h. . Solid rubiprostone was filtered, washed with n-heptane (2 mL) and dried under vacuum at 40 ° C. to give 0.32 g of solid rubiprostone.
¹ H NMR (300MHz, CDCl ₃ ): δ 4.19 (ddd, J = 11.4, 10.0, 7.2 Hz, 1H), 2.58 (dd, J = 17.6, 7.2 Hz, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.26 (dd, J = 17.7, 11.6 Hz, 1H), 2.10-1.75 (m, 7H), 1.72-1.45 (m, 7H), 1.45-1.22 (m, 8H,), 0.94 (t, J = 7.3 Hz, 3H)
m / z (ES-API, Neg): 389 ([MH] ^- , 100)

Example 20
Step 5b: Synthesis of rubiprostone via isopropyl ester of rubiprostone To a solution of isopropyl ester of rubiprostone (0.3 g), lipase PS SD (0.3 g) in acetone (1.5 mL) and pH 8.0 buffer (2 mL). ) Was stirred at 50-60 ° C. for 22 hours. The reaction solution was concentrated under reduced pressure at <50 ° C. to give 0.4 g of crude product, water (6 mL) and MTBE (6 mL) were added to the residue, stirred for 5 minutes, separated, The layer was extracted with MTBE (6 mL). The combined organic layers were washed once with water (6 mL) and once with brine (6 mL) and then concentrated under reduced pressure at <50 ° C. to give 0.3 g of crude product.

ＭｅＯＨ（１００ｍＬ）中におけるグアニジン塩酸塩（１０ｇ、０．１０５ｍｏｌ）の溶液に、ＭｅＯＨ（５０ｍＬ）中におけるＭｅＯＮａ（４．０ｇ、０．１０５ｍｏｌ）の溶液を約２５℃にて加えた。その溶液をこの温度で１時間攪拌し、白色固体が沈殿した。得られたスラリーをろ過し、沈殿したＮａＣｌを取り除き、グアニジンのＭｅＯＨ溶液を与えた。ＭｅＯＨ（２ｍＬ）中におけるルビプロストン（０．２ｇ、０．５１３ｍｍｏｌ）の溶液に、グアニジンのＭｅＯＨ溶液（０．７３ｍＬ、０．５１１ｍｍｏｌ）を約２５℃にて加えた。その混合物をこの温度で１時間攪拌し、次いで、溶媒を蒸発させた。残留物にＭＴＢＥ（２ｍＬ）を＜３０℃にて加え、真空下で蒸発させた。これを更に２回以上繰り返し、次いで、ＴＨＦ（２ｍＬ）を加えて、白色固体を生じさせた。約２５℃にて攪拌した後、その固体をろ過により単離し、ルビプロストンのグアニジン塩を白色固体として与えた。白色固体の^１Ｈ ＮＭＲ解析は、カルボキシラート基のメチレンシグナルαが遊離ルビプロストンと比べてシフトしたことを示した。
¹H NMR (300MHz, CD₃OD): δ = 4.22 - 4.10 (m, 1H), 2.48 (dd, J=17.4, 7.2 Hz, 1H), 2.19 (dd, J=17.4, 11.7 Hz, 1H), 2.16 (t, J=7.5 Hz, 2H), 2.10 - 1.26 (m, 22H), 0.93 (t, J = 7.2 Hz, 3H). Example 21
Step 6: Synthesis of rubiprostone salt

To a solution of guanidine hydrochloride (10 g, 0.105 mol) in MeOH (100 mL) was added a solution of MeONa (4.0 g, 0.105 mol) in MeOH (50 mL) at about 25 ° C. The solution was stirred at this temperature for 1 hour and a white solid precipitated. The resulting slurry was filtered to remove precipitated NaCl and give a guanidine in MeOH solution. To a solution of rubiprostone (0.2 g, 0.513 mmol) in MeOH (2 mL) was added guanidine in MeOH (0.73 mL, 0.511 mmol) at about 25 ° C. The mixture was stirred at this temperature for 1 hour and then the solvent was evaporated. To the residue was added MTBE (2 mL) at <30 ° C. and evaporated under vacuum. This was repeated two more times, then THF (2 mL) was added to give a white solid. After stirring at about 25 ° C., the solid was isolated by filtration to give the guanidine salt of rubiprostone as a white solid. ¹ H NMR analysis of the white solid showed that the methylene signal α of the carboxylate group was shifted compared to free rubiprostone.
¹ H NMR (300MHz, CD ₃ OD): δ = 4.22-4.10 (m, 1H), 2.48 (dd, J = 17.4, 7.2 Hz, 1H), 2.19 (dd, J = 17.4, 11.7 Hz, 1H), 2.16 (t, J = 7.5 Hz, 2H), 2.10-1.26 (m, 22H), 0.93 (t, J = 7.2 Hz, 3H).

（付記１４）
式Ｘの化合物を式ＩＩの化合物に転化させる工程ｃ）が、まず、式Ｘの化合物（ここで、Ｒ^７はＨである）の塩基及びベンジル化剤との反応によってＲ^７をＨからＲ^１４Ｂｎに転化し、式Ｘ’の化合物を生成することと、次いで、開始剤の存在下における式Ｘ’の化合物の三置換水素化スズとの反応によってＳｎＲ^８Ｒ^９Ｒ^１０を付け、式ＩＩの化合物を生成することとを含む、付記４に記載の方法。

（付記１５）
式Ｘの化合物を式ＩＩの化合物に転化させる工程ｃ）が、まず、式Ｘの化合物（ここで、Ｒ^７はＨである）の塩基及びベンジル化剤との反応によってＲ^７をＨからＲ^１４Ｂｎに転化し、式Ｘ’の化合物を生成することと、次いで、式Ｘ’の化合物の、Ｃｐ_２Ｚｒ(Ｈ)Ｃｌと、続いてＭｅＬｉとの反応によってＺｒＣｐ_２Ｍｅを付け、式ＩＩの化合物を生成することとを含む、付記４に記載の方法。

（付記１６）
式Ｘの化合物を式ＩＩの化合物に転化させる工程ｃ）が、まず、式Ｘの化合物（ここで、Ｒ^７はＨである）の塩基及びベンジル化剤との反応によってＲ^７をＨからＲ^１４Ｂｎに転化し、式Ｘ’の化合物を生成することと、次いで、Ｘ’の化合物の、Ｃｐ_２ＺｒＣｌ_２と、ｔ−ＢｕＭｇＣｌと、続いてＩ_２との反応によってＩを付け、式ＩＩの化合物を生成することとを含む、付記４に記載の方法。

（付記１７）
式ＩＩの化合物を式ＩＩＩに転化させる工程ｄ）が、式ＩＩの化合物（ここで、Ｒ^１５はＳｎＲ^８Ｒ^９Ｒ^１０又はＩであり、Ｒ^７はＢｎＲ^１４である）を、有機金属化合物と、続いてＭｅＣｕ(ＣＮ)Ｌｉ又は２−チエニルＣｕ(ＣＮ)Ｌｉと反応させることを含む、付記４に記載の方法。

（付記１８）
前記有機金属化合物がｔ−ＢｕＬｉ、ｓ−ＢｕＬｉ又はｎ−ＢｕＬｉである、付記１７に記載の方法。
（付記１９）
式（９）の化合物（７−((１Ｒ，２Ｒ，３Ｒ)−３−(ｔｅｒｔ−ブチルジメチルシリルオキシ)−２−(４，４−ジフルオロ−３−オキソオクチル)−５−オキソシクロペンチル)ヘプタン酸イソプロピル）。

（付記２０）
式（１０）の化合物（７−((１Ｒ，２Ｒ，３Ｒ)−３−(ｔｅｒｔ−ブチルジメチルシリルオキシ)−２−(４，４−ジフルオロ−３−オキソオクチル)−５−オキソシクロペンチル)ヘプタン酸）。

（付記２１）
式（７）の化合物（(Ｚ)−７−((１Ｒ，２Ｒ，３Ｒ)−２−((１Ｅ，５Ｅ)−３−(ベンジルオキシ)−４，４−ジフルオロオクタ−１，５−ジエニル)−３−(ｔｅｒｔ−ブチルジメチルシリルオキシ)−５−オキソシクロペンチル)ヘプタ−５−エン酸イソプロピル）。

（付記２２）
式Ｘの化合物（ここで、Ｒ^７はＨであり、二重結合が、Ｃ５とＣ６間若しくはＣ６とＣ７間に位置するか又は存在せず、ＩＭ５（(Ｅ)−４，４−ジフルオロオクタ−５−エン−１−イン−３−オール）、式ＩＭ５ｂの化合物（即ち、Ｘ；Ｒ^７＝Ｈ；４，４−ジフルオロオクタ−１−イン−３−オール）、式ＩＭ５ｃの化合物（即ち、Ｘ；Ｒ^７＝Ｈ、Ｃ６−Ｃ７二重結合；(Ｅ)−４，４−ジフルオロオクタ−６−エン−１−イン−３−オール）よりなる群から選択される）。

（付記２３）
ルビプロストンの塩を形成する工程を含む、ルビプロストンの精製方法。
（付記２４）
前記塩がグアニジン塩である、付記２３に記載の方法。 (Appendix)
(Appendix 1)
A method for synthesizing rubiprostone,
a) coupling cyclopentenone I with organocopper compound III to provide a compound of formula IV;
b) reacting a compound of formula IV with hydrogen in the presence of a catalyst to provide a compound of formula V;
c) oxidizing the compound of formula V to provide a compound of formula VI; and d) converting the compound of formula VI to rubiprostone.
(Appendix 2)
The method of claim 1, wherein step d) comprises hydrolysis of isopropyl ester with an enzyme.
(Appendix 3)
The method of claim 1, wherein step d) comprises the step of converting the compound of formula VI to the compound of formula VII.
(Appendix 4)
A process for the synthesis of a compound of formula III comprising
a) reacting a compound of formula VIII with a silyl protected metal acetylene compound of formula XI, where M is a metal ion, to provide a compound of formula IX;
b) treating a compound of formula IX with a reducing agent and a desilylating agent to provide a compound of formula X;
c) converting the compound of formula X to a compound of formula II; and d) converting the compound of formula II to formula III.
(Appendix 5)
The method of appendix 4, wherein M of the compound of formula XI is Li.
(Appendix 6)
The process of claim 4, wherein the reaction of the compound of formula VIII with the silyl protected metal acetylene compound of formula XI is carried out in the presence of a Lewis acid compound.
(Appendix 7)
The method according to appendix 6, wherein the Lewis acid compound is BF ₃ .
(Appendix 8)
The method according to appendix 4, wherein the reducing agent in step b) is a hydride reducing agent.
(Appendix 9)
The method according to appendix 8, wherein the hydride reducing agent is a metal hydride, and the metal is selected from the group consisting of aluminum, boron and ruthenium.
(Appendix 10)
The method according to appendix 4, wherein the desilylating agent in step b) is an alkoxide or fluoride reagent.
(Appendix 11)
The method according to appendix 10, wherein the alkoxide reagent is NaOMe.
(Appendix 12)
Method according to appendix 4, wherein step b) is carried out in one reaction vessel without isolating the intermediate.
(Appendix 13)
Step c) of converting the compound of formula X to the compound of formula II is first attached with SnR ⁸ R ⁹ R ¹⁰ by reaction of X with a trisubstituted tin hydride in the presence of an initiator to give a compound of formula II ′ And converting R ⁷ from H to R ¹⁴ Bn by reaction of a compound of formula II ′ with a base and a benzylating agent to produce a compound of formula II. Method.

(Appendix 14)
Step c) of converting the compound of formula X to the compound of formula II involves first converting R ⁷ from H to R by reaction with a base of the compound of formula X (where R ⁷ is H) and a benzylating agent. Conversion to ¹⁴ Bn to form a compound of formula X ′ and then reacting with a trisubstituted tin hydride of the compound of formula X ′ in the presence of an initiator to attach SnR ⁸ R ⁹ R ¹⁰ The method of claim 4, comprising producing the compound of II.

(Appendix 15)
Step c) of converting the compound of formula X to the compound of formula II involves first converting R ⁷ from H to R by reaction with a base of the compound of formula X (where R ⁷ is H) and a benzylating agent. Conversion to ¹⁴ Bn to produce a compound of formula X ′, and then attaching ZrCp ₂ Me by reaction of the compound of formula X ′ with Cp ₂ Zr (H) Cl followed by MeLi to give formula II The method of Claim 4 including producing | generating this compound.

(Appendix 16)
Step c) of converting the compound of formula X to the compound of formula II involves first converting R ⁷ from H to R by reaction with a base of the compound of formula X (where R ⁷ is H) and a benzylating agent. Conversion to ¹⁴ Bn to produce a compound of formula X ′ and then appending I by reaction of the compound of X ′ with Cp ₂ ZrCl ₂ , t-BuMgCl followed by I ₂ to give formula II The method of Claim 4 including producing | generating this compound.

(Appendix 17)
Step d) of converting the compound of formula II to formula III converts the compound of formula II where R ¹⁵ is SnR ⁸ R ⁹ R ¹⁰ or I and R ⁷ is BnR ¹⁴ into an organometallic compound And the subsequent reaction with MeCu (CN) Li or 2-thienyl Cu (CN) Li.

(Appendix 18)
The method according to appendix 17, wherein the organometallic compound is t-BuLi, s-BuLi, or n-BuLi.
(Appendix 19)
Compound of formula (9) (7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (4,4-difluoro-3-oxooctyl) -5-oxocyclopentyl) heptane Isopropyl acid).

(Appendix 20)
Compound of formula (10) (7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (4,4-difluoro-3-oxooctyl) -5-oxocyclopentyl) heptane acid).

(Appendix 21)
Compound of formula (7) ((Z) -7-((1R, 2R, 3R) -2-((1E, 5E) -3- (benzyloxy) -4,4-difluoroocta-1,5-dienyl) ) -3- (tert-butyldimethylsilyloxy) -5-oxocyclopentyl) hept-5-enoic acid isopropyl).

(Appendix 22)
Compound of Formula X wherein R ⁷ is H and the double bond is located or absent between C5 and C6 or C6 and C7, and IM5 ((E) -4,4-difluoroocta -5-en-1-in-3-ol), a compound of formula IM5b (ie X; R ⁷ = H; 4,4-difluorooct-1-in-3-ol), a compound of formula IM5c (ie ^{, X; R 7 = H,} C6-C7 double bond; (E)-4,4-difluoromethoxy oct-6-en-1-yn-3-ol) the group consisting of).

(Appendix 23)
A method for purifying rubiprostone, comprising a step of forming a salt of rubiprostone.
(Appendix 24)
24. The method according to appendix 23, wherein the salt is a guanidine salt.

Claims (4)

Compound of formula (9) (7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (4,4-difluoro-3-oxooctyl) -5-oxocyclopentyl) heptane Isopropyl acid).

Compound of formula (10) (7-((1R, 2R, 3R) -3- (tert-butyldimethylsilyloxy) -2- (4,4-difluoro-3-oxooctyl) -5-oxocyclopentyl) heptane acid).

Compound of Formula X wherein R ⁷ is H and the double bond is located or absent between C5 and C6 or C6 and C7, and IM5 ((E) -4,4-difluoroocta -5-en-1-in-3-ol), a compound of formula IM5b (ie X; R ⁷ = H; 4,4-difluorooct-1-in-3-ol), a compound of formula IM5c (ie ^{, X; R 7 = H,} C6-C7 double bond; (E)-4,4-difluoromethoxy oct-6-en-1-yn-3-ol) the group consisting of).

  A method for purifying rubiprostone, comprising a step of forming a salt of rubiprostone, wherein the salt is a guanidine salt.