Process for production of prostaglandin intermediates

Abstract: The isomer ratio of a cis-isomer against the corresponding trans-isomer with respect to the 5 - 6 double bond is improved in the production of prostaglandins, when a lactol is reacted with an ylide to cause simultaneously formation of the 5-double bond and an α-chain, whereby the ylide generated from a phosphonium salt with a potossium base, and a solvent which is liquid at the reaction temperature and has a dipole moment of 0.3 to 3.0D are used.

Description: BACKGROUND OF THE INVENTION The present invention relates to a process for the production of prostaglandin intermediates. A prostaglandin has a basic skeleton represented by the formula (c): A prostaglandin having a double bond between the carbon atoms of the 5 and 6 positions (referred to as the C 5 - C 6 position hereinafter, and this compound is hereinafter referred to as Δ 5 -PG), of which carbon atoms are located at the 2nd and 3rd positions counted from the carbon atom of the 5 membered ring having the α-chain linked thereto, has the cis- and trans-isomers. As the compound having a physiological activity is mainly a cis-isomer, it is important from the industrial standpoint to produce the cis-isomer in improved yield. Up to this time the introduction of the α-chain in the production of prostaglandins has been achieved as illustrated is the following scheme using Wittig reaction in which an ylide reacts with the lactol (d) having the ω-chain introduced therein: wherein X' is a protective group. In order to obtain Δ 5 -PGs which have a double bond between the C 5 - C 6 positions the lactol (d) is reacted with the ylide obtained from (4-carboxybutyl)triphenylphosphonium bromide, which is usually used in the form of a sodium salt of carboxylic acid produced by the reaction of (4-carboxybutyl)triphenylphosphonium bromide with sodium methylsulfinyl carbanion being obtainable from DMSO and NaH: Ph 3 P + C(Br - )H 2 (CH 2 ) 3 COOH → Ph 3 P=CH(CH 2 ) 3 COO - Na + This glide is reacted with the lactol in a solvent such as DMSO and the like. The reaction temperature is generally in the range from the ambient temperature to 70 °C. According to the above process which has conventionally been used for the introduction of the α-chain, the trans type Δ 5 -PGs (referred to as Δ 5 -trans-PGs) is present in the resutant product at a rate of about 10 % by weight. Consequently, it is absolutely necessary to purify the product when it is used as a starting material for drugs. In such purification the more impurity makes the less productivity. According to the present invention there is provided a process for the production of prostaglandin intermediates which comprises reacting a lactol represented by the following formula (I) or (I'): in which Y represents -CH 2 -CH 2 -, -CH=CH-, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH=CH- or -CH=CH-CH 2 - (in case of the formula (I') and Y being one of olefinic groups, Y represents cis-form one); R 1 represents a saturated or unsaturated aliphatic, alicyclic, aromatic, alkoxyalkyl, or aryloxyalkyl group either of which a number of carbon atoms of 1 to 12 and may have one or more substituent(s); R 2 represents an alkyl group having a number of carbon atoms of 1 to 4; Z represents a group which forms a cyclic acetal in cooperation with the carbon atom having Z attached thereto; and X represents a hydrogen atom or a group represented by the formula (a): R 5 OC(R 3 )(R 4 )- in which R 3 and R 4 represent independently a hydrogen atom or a C 1 - C 4 alkyl group; and R 5 represents a C 1 - C 4 alkyl, cyclohexyl, phenyl or benzyl group (R 4 and R 5 may cooperate with the other to form a ring), and an glide represented by formula (II): Ph 3 P=CH-Q-COO - K + in which Ph represents a phenyl group,; Q represents a saturated or unsaturated hydrocarbon group having a number of carbon atoms of 2 to 6 which may have one or more substituent(s), in an ethereal or aromatic solvent having a melting point of lower than -25 °C and a dipole moment of 0.3 - 3.0D and which contains a urea compound represented by the formula (b): (R 6 )(R 7 )N-CO-N(R 8 )(R 9 ) in which R 6 , R 7 , R 8 and R 9 represent an alkyl group having a number of carbon atoms of 1 to 2 (R 7 and R 8 each may cooperate with the other to form a ring), in addition to the ethereal or aromatic solvent. The feature of the present invention is in the use of a potassium carboxylate as an ylide and the selection of a specifically determined solvent and urea compound. The reduction in ratio of the trans-isomer is not observed when the DMSO which is conventionally the most commonly employed solvent for this reaction, is used as the solvent, even if a potassium carboxylate is used as an ylide, and such reduction is not observed as well, either when a lithium salt or a sodium carboxylate is used as the ylide, even if the solvent specified in the present invention is used. The lactol used in the present invention is represented by the formula (I) or (I'): in which Y represents -CH 2 -CH 2 -, -CH=CH-, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH=CH- or -CH=CH-CH 2 - (in case of the formula (I') and Y being one of olefinic groups, Y represents cis-form one);. R 1 is not restrictive, but may include any alkyl groups which are common in the ω-chains of prostaglandins. Typical examples of the groups are aliphatic, alicyclic, or aromatic groups, either of which have a number of carbon atoms of 1 to 12. A preferable aliphatic group is a saturated one which has a number of carbon atoms of 2 to 10, and more preferable one is a saturated hydrocarbon group which has a number of carbon atoms of 5 to 7. Examples of the substituents are methyl, ethyl, hydroxyl, methoxy, ethoxy, fluorine, chlorine and the like. Examples of the alicyclic hydrocarbon groups are cyclopropenyl, cyclopentyl, cyclohexyl and the like, which may be alkyl alicyclic groups such as alkylcyclopentyl. Examples of the aromatic groups are phenyl, tolyl, and the like, which may include aralkyl group such as benzyl and the like. R 1 may be an alkoxyalkyl group such as ethoxybutyl; an aryloxyalkyl group such as phenoxybutyl and the like. Substitution on the group R 1 or presence a double bond thereon does not exert any substantial influence on the isomer ratio of Δ 5 -cis-PGs against Δ 5 -trans PGs. R 2 is generally a C 1 - C 4 alkyl group which may be branched, but it is not restrictive. Z is a commonly used protective groups for the oxo group at the 15-position in the synthetic process of prostaglandins, and typically such groups as may fuse to the carbon atom at the 15- or 16-position in the ω-chain having Z attached to form a cyclic acetal. Specific examples of the cyclic acetals are exemplified as follows: X is a hydrogen atom or a protective group which is commonly used for protecting the hydroxyl group at the 11-position in the synthetic process of prostaglandins, typically a group represented by the following formula (a): R 5 OC(R 3 )(R 4 )- wherein the groups R 3 and R 4 are independently a hydrogen atom or an alkyl group having a number of carbon atoms of 1 to 4 which may be branched; and R 5 may be an alkyl group having a number of carbon atoms of 1 to 4, cyclohexyl, phenyl, benzyl group and the like, which may have one substituent(s) or more such as halogen atom or an alkoxy group and the like. R 4 and R 5 each may fuse to the other to form a ring. The examples of X may be tetrahydropyranyl, methoxymethyl, t-butoxymethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, and the like. The ylide (II) used in the present invention, represented by the following formula: Ph 3 P=CH-Q-COO - K + wherein Ph and Q are as defined above can be obtained, for instance, by the reaction of a phosphonium salt (III) represented by the formula: [Ph 3 P + CH 2 -Q-COOH](Hal) - wherein Ph and Q are as defined above, and Hal is a halogen atom, especially Br, Cl or I, with a suitable potassium base such as potassium t-butoxide, potassium hydride, potassium bis(trimethylsilyl)amide, potassium methoxide, potassium ethoxide, potassium n-butoxide and the like in an appropriate solvent. A sodium base has been conventionally used generate the glide, but it has been found that a potassium base is essential for preparing the Δ 5 -cis-PGs. The solvent used for the preparation of this glide is not restrictive, but it is advantageous to use the same solvent as the solvent used in the next reaction between the ylide and the compound (I) or (I'), because the ylide solution obtained can be used as such in the next reaction. The resultant ylide (II) is reacted with the lactol represented by the formula (I) or (I') in an aromatic or ethereal solvent, which has a melting point of lower than -25 °C, and a dipole moment of 0.3 to 3.0D. The reaction temperature is suitably in the range of about -25 °C to -40 °C. If it is higher than -25 °C, the production ratio of Δ 5 -cis-PGs to Δ 5 -trans-PGs becomes lower. The solvent used in the present invention has necessarily a melting point lower than the reaction temperature. The isonomer ratio and yield of Δ 5 -cis-PGs decrease when a solvent having a dipole moment lower or higher than the aforementioned range is used. A suitable solvent is ethereal or aromatic, and in the case of the former the dipole moment is more preferably 1.0 to 2.0, and in case of the latter it is more preferably 0.3 to 1.0. Specific examples of a preferable solvent used for the present invention include tetrahydrofuran (1.70D, mp: -108.5 °C), diethyl ether (1.12D, mp: -116.3 °C), dibutyl ether (1.22D, mp: -98 °C), diisopropyl ether (1.22D, mp: -85.89 °C), dimethoxy ethane (1.79D, mp: -58 °C), toluene (0.37D, mp: -94.99 °C), ethylbenzene (0.58D, mp: -95 °C), cumene (0.65D, mp: -96 °C) and the like. The particularly preferable solvent is tetrahydrofuran. The production ratio and the yield of Δ 5 -cis-PGs is improved by the combination of the aforementioned ethereal or aromatic solvent with the urea compound represented by the formula (b): (R 6 )(R 7 )N-CO-N(R 8 )(R 9 ) wherein R 6 , R 7 , R 8 and R 9 independently represent an alkyl group having a number of carbon atoms of 1 to 2 the R 7 and R 8 each may cooperate with the other to form a ring. Typical examples of the urea compounds are 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidine (DMPU), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,1,3,3-tetramethyl urea, 1,1,3,3-tetraethyl urea and the like. These urea compounds may be used in the amount of not more than 50 % by volume based on the total volume of solvent, usually 1 to 50 % by volume, more preferably 3 to 10 % by volume. The dipole moment and the melting point of the urea compounds themselves are not restrictive, but the melting point of the mixed solvent containing the urea compound should be lower than the reaction temperature. In the case where X is a hydrogen atom, the above urea compounds are preferably used. The solvent should be used in the amount sufficient to homogeneously dissolve the ylide (II) and the lactol (I) or (I') at the reaction temperature. It is used generally at a ratio of 5 to 100 ml per one gram of the lactol (I) or (I'). The reaction between the lactol (I) or (I') and the glide (II) is illustrated below: wherein X, Y, Z, R 1 , R 2 , Ph 3 and Q are defined above. Various kinds of prostaglandins and derivatives thereof can be prepared from the prostaglandin intermediates of the present invention in the conventional manner. Particularly, the intermediates are the useful for the raw materials of for the preparation of prostaglandins A 2 , D 2 , E 2 , F 2 and J 2 , and their various derivatives. The Examples are to be illustrated below to describe this invention more specifically. Example 1 Preparation of 13,14-dihydro-20-ethyl-15-keto-PGF 2 α isopropyl ester (4): 4-Carboxybutyltriphenylphosphonium bromide (1.03g, 2.32 mmol) and DMPU (1.6 ml) were added into a 100 ml round bottomed flask, into which potassium t-butoxide (1.0 M, 4.64 ml, 4.64 mmol) was added and stirred for 30 minutes. After the mixed solution was cooled at -35 °C, a solution (0.45 ml) of the lactol (1) (0.247 g, 0.58 mmol) in a solvent mixture of THF and DMPU (THF/DMPU = 3/1) (0.45 ml) and the solvent mixture of THF and DMPU (THF/DMPU = 3/1) (0.45 ml) used to wash the vessel of the lactol solution were added dropwise over 20 minutes. The reaction mixture was stirred for 15 hours. After the usual work-up, the crude carboxylic acid (2) was obtained. Yield: 1.21 g The crude carboxylic acid (2) (1.21 g) was esterified using DBU (0.26 ml) and isopropyl iodide (0.17 ml) in dry acetonitrile (5 ml) to give isopropyl ester (3). Yield: 0.2945 g (92 %) The isopropyl ester (3) was hydrolyzed with an acid to give 13,14-dihydro-20-ethyl-15-keto-PGF 2 α isopropyl ester (4). Yield: 0.2080 g, (92 %). The content of Δ 5 -trans-isomer was 1.1 % Example 2 Preparation 13,14-dihydro-20-ethyl-15,15-ethylenedioxy-PGF 2 α isopropyl ester (7): Dry THF (70 ml) was added into a four-neck flask, and potassium t-butoxide (9.31 g) was suspended in the THF under algon atmosphere. To the suspention were added (4-carboxybutyl)triphenylphosphonium bromide (17.5 g) and DMPU (2.12 ml), followed by stirring for one hour. The reaction mixture was cooled to -35 °C, followed by addition of a solution of the lactol (5) (3.00g) in dry THF (60 ml) cooled at -35 °C. The vessel of the lactol (5) was washed with THF (10 ml), and the wash was added to the reaction mixture. The reaction was stirred for 20.5 hours and the bath was gradually warmed to -10 °C during the reaction. After the usual work-up the crude carboxylic acid (6) was obtained. Yield: 4.22 g The crude carboxylic acid (6) (4.22 g) was esterified using DBU (8.87 ml) and isopropyl iodide (2.96 ml) in dry acetonitrile (21 ml) to give the isopropyl ester (7). Yield: 3.70 g (90.1 %). The content of Δ 5 -trans-isomer in the compound (7) was 3.3 % Example 3 Preparation of 13,14-dihydro-20-ethyl-15,15-ethylenedioxy-PGF 2 α isopropyl ester (7): The same manners and the same conditions employed in the Example 2 were carried out except that the lactol (5) (2.15 g) and DMEU (1.37 ml) were used, to give the ester (7). Yield: 2.48 g (84.3 %, in two steps). The isomer ratio of Δ 5 -trans-isomer against Δ 5 -cis-isomer was 3.1 % The trans/cis ratio was determined by measuring the each peak area of the cis and the trans isomers separated by the HPLC using an ultraviolet spectrophotometer. The correction of the ratio based on their adsorption coefficients was not made. Comparative Example Preparation of 13,14-dihydro-20-ethyl-15-keto-PGF 2 α methyl ester (16) The lactone (14) (1.22 g) was reduced by DIBAL-H (7.6 ml) at -78 °C in dry toluene (30 ml). After stirring for 45 minutes, methanol (10 ml) was added, followed by stirring for 80 minutes. Ether was then added to the reaction solution. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the lactol (5). Separately, sodium hydride (60 % dispersion in mineral oil, 1.15 g) washed with dry ether was suspended in dry DMSO (30 ml), and then heated at 65 - 70 °C for one hour. After the resultant was cooled to room temperature, a solution of (4-carboxybutyl)triphenylphosphonium bromide (6.4 g) in DMSO was added, followed by stirring for 40 minutes. Into the resultant solution was added dropwise a solution of the lactol (5) in DMSO. The reaction mixture was stirred overnight. The usual work-up gave a carboxylic acid (6). The carboxylic acid (6) was esterified with diazomethane to give a methyl ester (15), which was then purified with silica gel column. Yield: 1.29 g (82 %) The methyl ester (15) (1.06 g) was dissolved in a solvent mixture of acetic acid, water, and THF (3 : 1 : 1) (18 ml), and the solution was then kept at 50 °C for 3 hours. After the usual work-up, 13,14-dihydro-20-ethyl-15-keto-PGF 2 α methyl ester (16) was obtained. Yield: 0.868 g (74 %). The content of Δ 5 -trans-isomer in the compound (16) was found to be 9.3 %

Claims: A process for the production of prostaglandin intermediates which comprises reacting a lactol represented by the following formula (I) or (I'): in which Y represents -CH 2 -CH 2 -, -CH=CH-, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH=CH- or -CH=CH-CH 2 - (in case of the formula (I') and Y being one of olefinic groups, Y represents cis-form one); R 1 represents a saturated or unsaturated aliphatic, alicyclic, aromatic, alkoxyalkyl, or aryloxyalkyl group, either which have a number of carbon atoms of 1 to 12 and may have one or more substituent(s); R 2 represents an alkyl group having a number of carbon atoms of 1 to 4; Z represents a group which forms a cyclic acetal together with the carbon atom to which Z attaches; and X represents a hydrogen atom or a group represented by the formula (a): R 5 OC(R 3 )(R 4 )- in which R 3 and R 4 represent independently a hydrogen atom or an alkyl group having a number of carbon atoms of 1 to 4; and R 5 represents an alkyl group having a number of carbon atoms of 1 to 4, cyclohexyl, phenyl or benzyl group (R 4 and R 5 each may fuse to the other to form a ring), and an ylide represented by the formula (II): Ph 3 P=CH-Q-COO - K + in which Ph represents a phenyl group,; Q represents a saturated or unsaturated hydrocarbon group having a number of carbon atoms of 2 to 6 which may have one or more substituent(s), in an ethereal or aromatic solvent having a melting point of lower than -25 °C and a dipole moment of 0.3 - 3.0D and which contains a urea compound represented by the formula (b): (R 6 )(R 7 )N-CO-N(R 8 )(R 9 ) in which R 6 , R 7 , R 8 and R 9 represent an alkyl group having a number of carbon atoms of 1 to 2 (R 7 and R 8 each may cooperate with the other to form a ring), in addition to the ethereal or aromatic solvent. The process of the Claim 1, in which the solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, dipropyl ether, diisopropyl ether and toluene. The process of the Claim 1, in which the reaction is carried out at a temperature of from - 25 °C to -40 °C.

Inventors: ODA TOMIO, UENO RYUJI, ODA, TOMIO, UENO, RYUJI, ODA, TOMIO, UENO SEIYAKU SANDA
Applicants: R TECH UENO LTD, R-TECH UENO, LTD.
Application year: 1992
Main classification: C07D317
IPC codes: C07C59, C07D311, C07C69, C07D317, C07D407, C07C405