CZ305221B6 - Process for preparing (3aR,4S,5R,6aS)-4-[(3S)-5-cyclohexyl-3-hydroxypent-1-yn-1-yl]-5-(ethoxymethoxy)-hexahydro-2H-cyclopenta[b]furan-2-one - Google Patents

Abstract

The present invention provides a process for preparing (3aR,4S,5R,6aS)-4-[(3S)-5-cyclohexyl-3-hydroxypent-1-yn-1-yl]-5-(ethoxymethoxy)-hexahydro-2H-cyclopenta[b]furan-2-one 17 from gamma -lactone 11 by making use of a single protecting group, with a small number of steps and under moderate reaction conditions.

Description

Preparation of (3a, 4 ', 5', 5 '(1 ^' , 6aA) -4- (35) -5-cyclohexyl-3-hydroxypent-1-yn-1-yl | -5 (ethoxymethoxy) -hexahydro-2 H-cyclopenta [Z]] furan-2-one

Technical field

The invention relates to a novel process for the synthesis of a key intermediate for the preparation of non-halogenated prostaglandin alphaprostol.

BACKGROUND OF THE INVENTION

Prostaglandins (PG) are arachidonic acid-derived compounds. These substances are very similar to hormones but, unlike them, do not consist of specialized organs, are not transmitted by blood and act on the spot. Their effects vary according to where they work. They affect blood flow, production of a number of substances including hormones and digestive juices, blood coagulation, participate in immune and inflammatory processes, increase uterine muscle contractions, etc. Their excessive activity is inhibited by certain drugs, eg non-steroidal anti-inflammatory drugs such as ibuprofen. inhibition of prostaglandin biosynthesis (Rowson, LEA; Tervit, R .; Brand, AJ Reprod. Fert. 1972, 29, 145).

In 1972, prostaglandin F2 Alpha (PGF _2ot ) was found to cause luteolytic effects in cattle (Maffeo, G .; Redaelli, G .; Socci, A. Folia Veterinaria Latina, 1977, 7, 71). ). Since then, many substances of a similar structural formula have been used to influence the heat of cattle. Substances from this group were used to achieve gradual ovulation, shortening the lifetime of the yellow body. Control of heat with these substances brought the possibility of accurate timing of insemination, which greatly helped the reproductive management of cattle and cattle.

Structural formula of prostaglandin F2ot

Prostaglandin F2a

M: 368.51 g.mof ¹ CAS: 551-11-1

Alfaprostol, the full chemical name methyl (Z) -7 - [(l / ?, 2 S, 3 / ?, 5 »S ') - 2 - ^[(35) -5-cykloliexyl-3-hydroxy-l-pentynyl ] -3,5-dihydroxycyclopentyl] -5-heptanoate, is a known veterinary drug belonging to the prostaglandin family. Alfaprostol has proven to be more suitable than PGF _2a as synthetic prostaglandin and has also been used in cattle since 1983 (Howey, W .; Jochle, W .; Bames, W. Austr. Vet. J. 1983, 60, 180) and mare. . A detailed study has also elucidated its metabolism. (Kaykaty, M .; Weiss, G .; Barbalas, MJ Agric. Food Chem. 1986, 34, 688-694).

Structural formula of Alfaprostol:

Alfaprostol:

M: 406.56 g.mof ¹

CAS: 74176-31-1

Trademarks: Alfavet (Roche),

Alphacept

- 1 GB 305221 B6

For the synthesis of alphaprostol, the key intermediate of the Corey lactone skeleton with the attached ω-chain is:

where Prot is a protecting group.

Two possibilities for the preparation of the key intermediate are known in the art.

The basis of the first approach (Scheme 1, Gandolfi et al .: CH 617186 and Gandolfi et al .:

(U.S. Pat. No. 4,361,577) is the reaction of Corey lactone 1 with a suitable phosphonate 2a, 2b in the sense of the WittigHome reaction which provided an unsaturated ketone 3a or 3b. The bromo derivative 3b was also prepared by reaction with phosphonate 2a, with formation of bromo phosphonate 2b in situ using V-bromosuccinimide. Compound 3a was converted to bromo ketone 3b using pyrrolidone-2-hydrotribromide. This was followed by asymmetric reduction to the corresponding alcohol 4a, 4b and replacement of the existing O-benzoyl protecting group with a tetrahydropyranyl protecting group (THP) to give intermediates 5a, 5b.

a: X = H and: X = H b: X = Br b: X = Br

Scheme 1: Synthesis of intermediate 5a - 5b.

Intermediate 5b was converted to pyrrolidone-2-hydrotribromide either to dibromo compound 6 or directly with aqueous sodium hydroxide to dehydrohalide form 7. Compound 6 was also obtained by reacting derivative 5a with elemental bromine. Treatment of dibromine 6 with aqueous sodium hydroxide also yielded the target intermediate 7 (Scheme 2).

-2GB 305221 B6

5a-5b a: X = H b: X = Br

Scheme 2: Preparation of the dehydrohalogenated intermediate 7.

A Second Approach to Literature (Scheme 3, Klar, U .; Pletsch, A .; Skuballa, W .; Vorbriiggen, H. Bioorganic & Medicinal Chemistry Letters. 1992, 2 (5), 445-448 and Klar, U .; Deicke P .; Pletsch, A. Synthetic Communications 1993, 23 (22), 3185-3189) is based on the same aldehyde 1 as the above-mentioned patents. By bromo succinimide, bromine is generated in situ, which selectively bromo is the appropriate phosphonate to form the bromo derivative, which is then reduced to the alcohol 8. Diol 9 was obtained by basic hydrolysis, and further, without protecting the hydroxy groups, by reaction with CsOAc in toluene in the presence of 18-Crown-6 ether dehydrohalogenated to the diol 10. This approach does not describe the synthesis of the key intermediate for the preparation of alphaprostol, but the key preparation of the triple bond of the intermediate.

Scheme 3: Preparation of the dehydrohalogenated intermediate 10.

The R groups used for alcohol 8, 9 and 10 are summarized in Table 1.

-3GB 305221 B6

Table 1: Chains used for alcohols 8, 9 and 10. 5

SUMMARY OF THE INVENTION

The present invention provides a process for preparing (3aR, 4S, 5R, 6aS) -4 - [(3S) -5-cyclohexyl-3-hydroxy-10-pent-1-yn-1-yl] -5- (ethoxymethoxy) -hexahydro-2H- cyclopenta [b] furan-2-one, which is characterized in that gamma-lactone-A (-) 11, which can be prepared according to Weidner (J. Weidner et al .: Liebigs Ann. Chem. 1991, 1301 ) or according to Veselý et al. (I. Vesely et al .: AO 226905), O

O

o reacting with chloromethyl ethyl ether (EOM-CI) in the presence of diisopropylethylamine (DIPEA) in dichloromethane (DCM) to form the protected lactone 12,

which is subsequently deacetylated in anhydrous methanol in the presence of anhydrous potassium carbonate to give alcohol 13,

and the alcohol 13 obtained is oxidized with Dess-Martin periiodomethane in dichloromethane to the corresponding aldehyde 14,

-4GB 305221 B6

subsequently, the aldehyde 14 is reacted with dimethyl 4-cyclohexyl-2-oxobutylphosphonate in dimethoxyethane (DME) and in the presence of N -bromosuccinimide to give (3aR, 4S, 5R, 6aS) -4 [(1Z) -2-bromo-5 -cyclohexyl-3-oxopent-1-en-1-yl] -5- (ethoxymethoxy) hexahydro-2H-

which is then converted to the corresponding hydroxy derivative 16 by reduction,

and finally the hydroxy derivative 16 is dehydrohalogenated with tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF) to give (3aR, 4S, 5R, 6aS) -4 - [(3S) -5-cyclohexyl-3-hydroxypent-1-yn-1-yl -5- (ethoxymethoxy) -hexahydro-2H-cyclopenta [b] furan-2-one 17.

The process according to the invention thus provides the key intermediate 17 for the preparation of alphaprostol, which is characterized by a complete ω-chain. This intermediate, after deprotection of the EOM protecting group, can be used to synthesize the alphaprostol molecule by known or novel synthetic procedures.

An advantage of the process of the invention is the preparation of 17 using mild reaction conditions, fewer synthetic steps and using a single protecting group. Also used are agents that cannot cause racemization of the individual intermediates.

-5GB 305221 B6

The invention is further illustrated by the following examples without limiting the scope thereof.

DETAILED DESCRIPTION OF THE INVENTION

Instruments and methods

All commercially available chemicals were purchased from Sigma Aldrich and TCI. Column chromatography was performed on silica gel (SiO ₂ 60 Å, particle size 0.060-0.200 mm, Acros Organics) using commercially available solvents. Thin-layer chromatography was performed on aluminum plates coated with silica gel (SiO ₂ 60 F 254 (Merck)) visualized by UV lamp (254 or 360 nm) or ethanolic phosphomolybdic acid solution. ¹ H and ¹³ C NMR spectra were measured at 25 ° C on a Bruker AVANCE III 400 at 400.13 MHz for 1 H and 1 H respectively. 100.62 MHz for ¹³ C. Chemical shifts are reported in ppm relative to the mean signals of the solvents used, CDCl ₃ and DMSO-d 6. Coupling constants (J) are given in Hz. The observed signals are described as s (singlet), br (broad singlet), d (doublet), t (triplet), and m (multiplet).

Example 1

Preparation of [(3R, 4S, 5S, 6R) -5- (ethoxymethoxy) -2-oxohexahydro-2H-cyclopenta [furan-4-yl] methyl acetate (12)

To a 100 mL single neck flask was added gamma-lactone-A (-) 11 (0.023 mol), which was dissolved in DCM (45 mL) at room temperature. The solution was cooled below 5 ° C and DIPEA (0.058 mol) was added followed by EOM-C1 (0.051 mol). After addition of both reaction components, the cooling bath was removed and the mixture was allowed to stir overnight at room temperature. The next day, water (25 mL) was added to the reddish solution, and the mixture was extracted with ethyl acetate (EtOAc) (3 x 40 mL). The organic extracts were combined and dried. The product was isolated by column chromatography (EtOAc: n-Hexane; 1: 1). Product 12 was obtained as a yellowish oil in 95% yield.

Product characterization: Rf: 0.3 (EtOAc: n-Hexane; 1: 1). 1 H NMR (400 MHz, CDCl 3): δ 4.92 (1H, m), 4.61 (2H, m), 4.00 (1H, m), 3.95 (2H, m), 3.58-3.49 (2H, m), 2.77 (1 H, m), 2.66 2.60 (1 H, m), 2.52 - 2.47 (1 H, dd, J = 18.2 Hz, J = 2.64 Hz), 2.31-2.18 (2 H, m), 2.10 (1 H, m), 2.02 (3H, s); 1.15 (3H, t, J = 7.08 Hz). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 176.6, 170.7, 94.1,83.5, 78.9, 63.9. 63.5. 51.3, 39.9. 37.9, 35.3, 20.8, and 15.0.

Example 2

Preparation of (3R ^, 4R ^, 5R, 6aA) -5- (Ethoxymethoxy) -4- (hydroxymethyl) hexahydro-2H-cyclopenta [furan-2-one] (13)

-6GB 305221 B6

EOM-gamma-lactone-A (-) 12 (0.004 mol) was suspended in MeOH (35 ml) in a 100 mL single neck flask. K ₂ CO ₃ was then added in one portion and the heterogeneous mixture was heated at 35 ° C (TLC), EtOAc: n-Hexane mobile phase; 1: 1, detection with 5% ethanolic phosphomolybdate acid solution). After disappearance of the starting material from the reaction mixture (ca. 3 hours), the solvent was evaporated and the product was isolated by column chromatography (EtOAc: n-Hexane, 3.5: 0.5). Product 13 was obtained as an oil in 76% yield.

Product characterization: Ff: 0.2 (EtOAc: n-Hexane; 3.5: 0.5). 1 H NMR (400 MHz, CDCl 3): δ 4.92 (1H, m), 4.64 (2H, m), 4.01 (1H, m), 3.60-3.53 (4H, m), 2.78 (1H, m), 2.70 ( 1 H, m), 2.52 - 2.47 (1 H, dd, J = 17.64 Hz, J = 2.2 Hz), 2.40 (1 H, br), 2.33 - 2.26 (1 H, m), 2.12 - 2.04 (2 H, m), 1.18 (3H, t, J = 7.14Hz). ¹³ C NMR (100 MHz, CDCl 3): δ 177.3, 94.3, 83.9, 79.7, 63.6, 62.6, 54.1, 39.3, 38.2, 35.4, 15.0.

Example 3

Preparation of (3α7β, 45.5β, 6αSj-5- (ethoxymethoxy) -2-oxohexahydro-2 H) -cyclopenta [6] furan-4-carbaldehyde (14)

O

DMP, NaHCO ₃ DCM. 24 h 25 ° C

O

A 250 mL three-necked flask equipped with a thermometer was charged with alcohol 13 (0.029 mol), which was dissolved in DCM (100 mL). The solution was cooled to 0 ° C and finely ground NaHCO ₃ (0.143 mol) was added in one portion followed by small portions of Dess-Martin periodinane (0.044 mol). The cooling bath was removed and the heterogeneous mixture was stirred at room temperature overnight. The next day, a 10% Na ₂ S ₂ O ₃ solution (50 mL) was slowly added to the reaction mixture. After 20 minutes of vigorous stirring, the organic layer was separated. Subsequently, the organic layer was extracted with a 10% Na ₂ SO ₂ O ₃ solution (3 x 50 mL) followed by distilled water (2 x 50 mL). The combined aqueous extracts were extracted with DCM (1 x 50 mL). The combined organic extracts were dried over Na ₂ SO ₃ and evaporated in a vacuum rotary evaporator (bath temperature 40 ° C) to give product 14 as an oil in 97% yield. The product was used immediately for the next reaction step.

Product Characterization: 1 H NMR (400 MHz, CDCl 3): δ 9.69 (1H, s), 5.00 (1H, m), 4.67 (2H, m), 4.47 (1H, m), 3.58 (2H, m), 3.36 (1H, m), 3.06 (1H, m), 2.90 - 2.82 (1H, m), 2.49 - 2.44 (1H, m), 2.31 - 2.27 (1H, m), 1.87 - 1.80 (1H, m) 1.18 (3H, t, J = 7.01Hz). ¹³ C NMR (100 MHz, CDCl 3): δ 199.0, 176.6, 94.3, 84.3, 77.9, 65.6, 63.9, 38.0, 36.6, 35.5, 15.1.

-7 GB 305221 B6

Example 4

Preparation of (3α, 4α, 4α, 5α, 6α.S ') -4- (2Z) -2-bromo-5-cyclohexyl-3-oxopent-1-en-1-yl] -5- ( ethoxymethoxy) -hexahydro-2H-cyclopenta [6] furan-2-one (15)

To a suspension of NaH (0.022 mol) in DME (50 mL) at 0 ° C was added a solution of N-bromosuccinimide (0.022 mol) in DME (40 mL) and dimethyl 4 solution at 0 ° C in a 250 mL three-necked flask equipped with a thermometer, stirrer and N ₂ inlet. -cyclohexyl-2-oxobutylphosphonate (0.024 mol) in DME (20 ml). This solution was stirred at the same temperature (0 ° C) for 1 hour. A solution of aldehyde 14 (0.022 mol) in DME (20 ml) was then added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 90 minutes. After this time, the solution was poured into 100 mL of distilled water and extracted with EtOAc (3x 70 mL). The combined organic extracts were dried over Na ₂ SO ₄ and the product isolated by column chromatography (mobile phase n-Hexane: EtOAc; 3: 1). The product was obtained as an oil in 60% yield.

Product Characterization: 1 H NMR (400 MHz, CDCl ₃ ): δ 6.83 (1H, d, J = 9.06 Hz), 5.05-5.02 (1H, m), 4.65 (2H, m), 4.41 (1H, m), 3.96 (1H, m), 3.88-3.88 (2H, m), 3.62-3.52 (1H, m), 3.20 (1H, m), 2.83 -2.75 (1H, m), 2.27 (2H, m), 1.71- 1.61 (6H, m), 1.23-1.13 (10H, m), 0.95-0.83 (2H, m). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 195.0, 33.2, 33.1, 31.8, 31.2, 26.6, 26.3, 15.2.

Example 5

Preparation of (3α, 4α, 4α, 5α, 6αS) -4 - [(1Z, 3S) -2-bromo-5-cyclohexyl-3-hydroxypent-1-en-1-yl] -5- ( ethoxymethoxy) -hexahydro-277-cyclopenta [n] furan-2-one (16)

To a 50 mL three-necked flask equipped with a thermometer was placed ketone 15 (0.0026 mol), which was dissolved in MeOH (20 mL). The solution was cooled to -40 ° C and NaBH ₄ (0.0025 mol) was added slowly. The mixture was stirred at the same temperature for 1 h. After this time, 5 drops of glacial acetic acid were added and all MeOH was evaporated. The residue was extracted with EtOAc (3 x 50 mL). The product 16 was isolated by column chromatography (EtOAc: n-Hexane; 1: 1) and was isolated as a colorless oil in 16% yield.

Product characterization: Rf: 0.48 (EtOAc: n-Hexane; 1: 1). 1 H NMR (400 MHz, CDCl ₃ ): δ 5.74 (1H, d, J = 8.69Hz), 5.00-4.98 (1H, m), 4.66 (2H, m), 4.04-4.00 (2H, m) 3.60 - 3.55 (2H, m), 2.83 - 2.76 (1H, m), 2.64 - 2.67 (1H, m), 2.64 - 2.59 (1H, m), 2.21 (2H, m) 2.10 (1H, br), 1.69-1.56 (6H, m), 1.23-1.08 (10H, m), 0.89-0.82 (2H, m). ¹³ C NMR (100

-8EN 305221 B6

MHz, CDC1 _3): δ 176.8, 134.3, 128.9, 93.8, 83.6, 81.6, 76.7, 63.6, 53.7, 43.6, 38.1, 37.4, 35.1, 33.3,32.9,32.8, 26.6, 26.3, 15.0.

Example 6

Preparation of (3a R, 4 S ₁ ', 57?, 6a4S) -4 - [(3 S) -5-cyclohexyl-3-hydroxy-pent-l-yn-l-yl] -5- (ethoxymethoxy) hexahydro-27 / - cyclopenta [Z>] furan-2-one (17)

To a 50 mL single neck flask was added alcohol 16 (0.00022 mol), which was dissolved in THF (10 mL) and a 1M solution of TBAF-3H ₂ O in THF (0.0011 mol) was added in one portion. The solution was heated at 60 ° C for 4 hours (reaction control: TLC, EtOAc: n-Hexane phase; 1: 1, detection with 5% ethanolic phosphomolybdate) solution). After cooling, 20 mL of water was added to the reaction mixture, and the solution was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over Na ₂ SO 4 and product 17 isolated by column chromatography (n-Hexane: EtOAc; 2: 1). A colorless oil was obtained in a yield of 30%.

Product characterization: Rf: 0.4 (EtOAc: n-Hexane; 1: 1). 1 H NMR (400 MHz, CDCl 3): δ 5.11

- 5.07 (1 H, m), 4.70 - 4.66 (2 H, m), 4.29 (1 H, m), 4.22 - 4.19 (1 H, m), 3.62 - 3.55 (2 H, m), 3.07

- 3.02 (1 H, m), 2.88 (1 H, m), 2.81 (1 H, m), 2.57 - 2.52 (1 H, m), 2.28 (2 H, m), 1.77 (1 H, br), 1.70-1.61 (6H) m / z, 1.30 - 1.14 (10H, m), 0.91-0.86 (2 H, m). ¹³ C NMR (100 MHz, CDCl ₃ ): δ 176.8, 94.1, 84.9, 84.2, 84.0, 82.5, 63.9, 63.9, 62.9, 44.8, 44.1, 37.8, 37.5, 35.5, 33.5, 33.4, 32.9, 26.7, 26.4, 15.2.

Claims (1)

PATENT CLAIMS Process for the preparation of (3aR, 4S, 5R, 6aS) -4 - [(3S) -5-cyclohexyl-3-hydroxypent-1-yn-1-yl] -5 (ethoxymethoxy) -hexahydro-2H-cyclopenta [b furan-2-one, characterized in that gamma-lactone-A (-) 11 is reacted with chloromethyl ethyl ether in the presence of diisopropylethylamine in dichloromethane to form the protected lactone 12, -9EN 305221 B6 which is subsequently deacetylated in anhydrous methanol in the presence of anhydrous potassium carbonate to give alcohol 13, 5 and the obtained alcohol 13 is oxidized with Dess-Martin periiodonate in dichloromethane to the corresponding aldehyde 14, followed by reaction of the aldehyde 14 with dimethyl 4-cyclohexyl-2-oxobutylphosphonate in dimethoxyethane and in the presence of N -bromosuccinimide to give (3aR, 4S, 5R, 6aS) -4 - [(1Z) -21Bromo-5-cyclohexy-3-oxopent-1-en-1-yl] -5- (ethoxymethoxy) hexahydro-2H-cyclopenta [b] furan-2 -onu 15, Finally, the hydroxy derivative 16 is subjected to dehydrohalogenation with tetrabutylammonium fluoride in tetrahydrofuran to give (3aR, 4S, 5R, 6aS) -4 - [(3S) -5-cyclohexyl-3-hydroxypent-1-yn-lyl] - 5- (ethoxymethoxy) -hexahydro-2H-cyclopenta [b] furan-2-one 17.