DE2246408A1 - PROCESS FOR THE SEPARATION OF RACEMISCHER 2- (2BETA-BENZYLOXYMETHYL-3ALPHA-HYDROXY4-CYCLOPENTEN-1ALPHA-YL) -ACETIC ACID - Google Patents

Description

LAWYER
DR. JUR. DIFÜ
ALFRED HO> /
DR. JUR.
DR. JUR.

: hem. Walter BEiI Sep. 20 1972

HMER

ZI ! SM. RJ. WOLPP CHR. AX

FRANKFURTAM MAIN-HIGH? AD £ LONSlitA3SE58

Our Mr. 18 176

Pfizer Inc.
New York, Η.Ϊ., V.St.Ä.

Process for the resolution of racemic 2- (2ß-benzyloxymethyl -hydroxy-4-eyclopenten ~ iC <-yl) -esüigsäure.

The present invention "relates to a process for separating the Z- (2ß-benzyloxymethyl-3C ^ -hydroxy-4-cyclopenten-1 ςΛ-yl) -etsaetic acid into the optically active components" or Antipodes. These compounds serve as key connections in the synthesis of trostaglandins according to Oorey.

The synthesis of prostaglandin E ₁ in optically active porm was a "remarkable achievement by EJ üorey et al., J. Aflier. Chem. Soc. 9J _- , 535 1969. The synthesis stages are in particular mild and specific reaction conditions

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marked. The further progress of prostaglandin research was severely hindered by the lack of a simple, versatile and technically feasible synthesis for the optically active forms of P (Ju ₂ and other natural prostaglandins ?! such as PGE ₁ , PGB ' _2cA , PGF ₁ ^, PGA ₂ and KiA

The lack of a simple method for the preparation of the critical hydroxy acid 2 ~ (2β ~ £ enzyloxymethyl-3fci-ÜydxOsy-4-cyelopenten-1 ^ t-yl) acetic acids in their antipodes constituted a major obstacle in Corey's relir step process for production of prostaglandin. 3Jia (+) -hydroxy acid leads to the prostaglandins »whose physiological importance is already known» while the (-) - hydroxy acid can be used for the synthesis of prostaglandins, whose physiological role "is still unknown.

The present invention now makes a technically authentic one Production of prostaglandins made possible.

As is known, members of the family of naturally occurring prostaglandins and their analogues show valuable therapeutic properties as contraceptives, ham ijinaatz against high blood pressure, diseases of the respiratory system, stomach ulcers and thromboses.

The present invention relates to a process for the resolution of racemic 2- (2β-benzyloxymethyl-5oC-hydroxy-4-cyclopentene-10 ^ -yl) acetic acid in the antipodes, which is characterized by the fact that one has the d (+) - amphetamine salt of this Acid from ethylene dichloride, dioxane, iithylene dichloride / ethylene chloride or l'etramethylene dichloride / chloroform in a period of time from to zii about 18 hours fractionally cristalized and separating the resulting crystalline salt. The invention also relates to the conversion of the ü (+) -Aniphetaniinsalzes into the free optically active acid. l> the volume never receives from

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Ethylene dichloride to ethylene chloride or from! Etramethylene dichloride to Chloroform "is preferably about 2: 1 .. ~ The crystallization is preferably carried out at a concentration of about 3 Ms 10 pounds (weight / volume). .,

According to a "preferred embodiment of the invention, the racemic acid is first yellow in ethylene dichloride + e.g. , with heating to the reflux temperature, then the solution is dried, filtered and concentrated. This solution is given further ethylene dichloride and then the d (+) -Amphetaiiiin added. The mixture is heated to about 6o G, inoculated with "already isolated (+/- amphetamine salt and then cooled for 3 hours to over eighth). Another solution can be done by additional recrystallization from ethylene dichloride, if necessary. -,

Perner can solve the raeeinische acid in ethylene dichloride and perform all! Olgestufen using dioxane, whereby äa.z last recrystallization Diöxan done.

According to a further embodiment of the invention, the racemic acid is first dissolved in riethylene chloride, then the d (+) -amphetamine iii ethylene dichloride is added and the final recrystallizations also take place aua Ethylene dichloride, the d (+) - metamine can also be found in a mixture of ethylene dichloride and Ilethylene chloride (2: 1) and the last UmlcciGtallisierung from ö-ieseia solution Carry out a mix of agents.

According to a further variant, the racemic acid is used first dissolved in ethyl chloride, then the d (+) - amphetamine added in setramethylene dichloride and the last recrystallizations are made from a mixture of 2etramethylenedi-

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Chloride and chloroform (2: 1).

In all these cases, the crystallization is preferably wipe at concentrations from about 3 to 1ο '; ό (weight / volume) is carried out, regardless of the particular solvent or *] Lösungsmittelgemisehe.

Me Kristallisationsetufe can be carried out at a temperature between about -1ο and +60 ⁰ C ", however, is usually eweckmäßigerweise carried out between about 25 and 60 ⁰ C · Crystallization usually requires about 2 to about 18 hours. Allowing the crystallization mixture to stand for a long time appears to be disadvantageous, since the product can be contaminated by the sale of the undesired isomers.

The starting material of the process according to the invention, ie 2- (2β-benayloxy-methyl-3öt-hydroxy ^ -cyelopenten-krtyl) acetic acid, is obtained by treating the corresponding ammonium salt with hydrochloric acid according to the instructions in the following examples. The preparation of the ammonium salt was described by Corey et al., J. Amer. Chem. Soc. $ £, 2586 (I97o) described. ■

Of course, the d (+) -araphetamine salJ5 can then converted into the optically active free acid by dissolving in water, acidifying with hydrochloric acid and extracting in ether will.

example 1

In a 500 ml Erlenmeyer flask, 22.6 g (0.081 col) de; -. Ammonium salt of the 2 - / "2ß-Bem.yloxymeth3'-l-3o (- 'hydroxy 4-cyclopenten-1 <X -ylj-acetic acid and 15 & _f 6 ml V / a & ser incorporated-

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fills. The mixture is then "stirred at room temperature." 16.2 ml (0.0972 KoI) 6N hydrochloric acid were added.

This mixture is extracted 4 times with 50 ml of ethylene dichloride, then the ethylene dichloride phase is washed 2 with water. The product is dried over magnesium sulfate, filtered and divided into 2 equal portions.

A portion of this product, ie 134 ml of solution, is concentrated in vacuo to give 11.7 g of an oil. This oil is dissolved in 1.06 ml of ethylene dichloride, the solution is heated to 60 G on a steam bath, and 5.48 g (0.04o5 mol) of d (+) - amphetamine are then added dropwise. The warm solution is inoculated with d (+) - amphetamine salt and cooled overnight. The resulting dried solid weighed 7.85 g (98? B yield), melting point 1ο6-ΐο8 ^ο 0, / "0 ^ 7 ^ ⁵ = + 7, S4 ° (c = 1, heüll)

The purification was carried out by recrystallizing twice from ethylene dichloride (1 g of amphetamine salt in 10 ml of solvent). The obtained pure d (+) - amphetamine salt (5.64 g, 71; ö yield) melted at 114-116 ⁰ C, / "θΓ7ρ ⁵ = I6,7 ° (c = 1, KeOH).

Example 2.

Following the procedure of Example 1, 22.6 g of the starting material were obtained transferred into an ul, the oil was divided into 2 portions.

A portion of 12.6 g was dissolved in 40 ml of ethylene dichloride, then 5.48 g of d (+) - amphetamine were added. The mixture was inoculated with d (+) - amphetamine salt which had already been isolated and refrigerated overnight. The resulting solid weighed 8.55 pounds after drying (I06CJ Ausbetite), melting point I08-II0 C,

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2246A08

LTtI ⁵ = ⁶ »4o ° (c = 1, HeUH)

8 & obtained of no d (+) -Aiaphetarainealzes were in 16o ml j-thylendichlorid (ratio 1: 2o) dissolved at 60 ⁰ G, then the solution was maintained at monitored itauintemperatur, filtered, V, and dried to thereby give 6, 68 g (84 $ yield) of the d (+) - amphetamine salt of F. 1o5-1o8 ü, / "^ _- T ₁ ) = + 10.7 ° (c m 1, KeOH). Weight ratio 1: 2o) gave 3.49 g (44% yield) of the pure d (+) - amphetainine salt with the data / " ⁰ LTJp = + 16.3 ° (c« 1, MeOH), m.p. 114-11 6 ⁰ C. A further 11.95 β des oles were dissolved in 7 o ml of Iiioxan, then 5.4k gd (+) - amphetamine was added to the solution. The mixture was inoculated as described above and cooled overnight. After drying, the resulting solid weighed 3.5 g (44% yield, m.p. 109-112 ° C.), foCJ ^ = + 8.38 ° (c = 1, KeOH). iiiin v / more limcrystallization from di.oxane (1: 1o) gave 1.02 g (3) 3; j) of the pure d (+) -amphetamine salt with a temperature of 109-114 ° C, Z "" ° L7p ⁵ = + 14.67 ° (c »1, KeOh).

Example 3

üach the procedure of Example 1 is again the starting oil was prepared, and 6.3 g thereof was transferred to 159 ml üthylendichloriä at 60 ⁰ C, treated with d (+) - amphetamine was added and then kept guard (about 18 hours) at iiauiutemperatur. The solution was then filtered and the residue was dried, giving 2.54 g (64% yield) of the d (+) - amphetamine salt with a melting point of 10-2-1o5 ° C, £ ~ O (J ^ ⁵ = + 6 , 58 ° (c = 1, MeOii). After recrystallizing once from ethylene dichloride, the pure d (+) -amphetainine salt with the data JpXJjf = + 16.3 ° G (c = 1, Ileoii), F. 114- 116 ⁰ C received.

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■ ■ "■ ⁷ - · 224B4Q8

Example 4. . '

In a 5oo ml Brlenmeyer flask were added 22.6 g of Aubgangümaterials of Example 1 and 158.6 ml ^H ¥ ater · filled. The mixture was "stirred at low temperature" until the solution had entered, then 3% 5 ml of 10% hydrochloric acid were added, the solution was extracted 4 times with 5 o ml of diethylene chloride each time, the methylene chloride phase became 2 ° washed with water, dried over magnesium sulfate and filtered off.

116 ml of this solution were concentrated in vacuo to 11.96 g of a UI. This oil was dissolved in 42.4 ml of ethylene dichloride and the solution was heated to 6o C on a steam bath, then 5-48 g (0.04o5 mol) of d (+) - amphetamine in 63.6 ml of ethylene dichloride were added to the warm Solution added dropwise. The solution was then inoculated with d (+) - amphetamine salt which had already been isolated and cooled with a haem. The resulting Pe st off v / og after drying 9, ο 5 g (111.2 ^ yield), ϊ. 93-1 o3 ° 0 / o (J ^ ⁵ _e 6.92 (c = 1, MeOH).

It was then recrystallized 3 times from ethylene dichloride (weight ratio 1: 1o), giving 4.89 g (61.55 »yield) of the pure d (+) - amplietamine salt of Ϊ ¹ .- 114-116 G, + ¹⁶ » ⁶ ° ( ^c = ¹ »

Example 5

In a 500 ml Lrlenmeyer flask was added 11.3 g of the starting material from Example 1 and 79.3 ml of water poured in. The mixture was at room temperature until the solution was complete stirred, then 8.1 ml of 6N, hydrochloric acid were added. The solution was then extracted 4 x with 25 ml of ethylene chloride each time,

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the Lethylenclilorid-Iliase was χ 2 with l / ater, dried over lia ^ ^ nesiumsulfat etz'ocknet, filtriei't and in ^2: split equal portions.

One portion was concentrated in vacuo to 6.3 β of an oil. . of Cl was dissolved in 55 ml of tetramethylene dichloride .und. warmed to 6o Ö on a steam bath. Bann were 2.74 g (o, o21 IiOl) ö (+) -amphetamine in 18 ml of Tetramethylencliplilorid v / poor Lc:> ung added dropwise. This was then inoculated as in the previous examples and cold-treated with Häcjit? Splits. The resulting dried solid weighed -6.9 g (88 °,:, Yield, mp 98-1o5 ° C), / o ^ TJp «5.196 ° (c« 1, Ixeüli).

The second portion of the solution was concentrated in vacuo to 6.2 g of an oil. Using the above measures and the same quantities of iteagents, 4.53 g (114, "yield) of a solid" were obtained; from I ¹ . 1o2-1o4 ^Q C, / ~ fc (j | ⁵ = 7.03 ° (c = 1, ijeül-l).

When recrystallizing from a 2: 1 mixture of tetramethylene dichloride and chloroform (1 g in 15 ml of the solvent mixture) 1.92 g (26? i) of product of 3? 'were obtained therefrom. 1o4-1o6 ° C Z "oL7 ^ = + S, 12 ° (c = 1, leÜH).

Further recirculation from the same solvent mixture gave 1.159 g (2o, 1 yield) of the pure α (+) -amphetamine salt of I; ^1st 112-115 ° C, / b (_7 ^ ⁵ = 15.7 ° (c = 1,

Example 6

The starting material from Example 1 (11.3 g) was dissolved in 79.5 ml of acid at room temperature, then 8.6 ml of 6n-oal acidic acid were added dropwise. The solution was given 4 times with ■■. $ &; 25 ^:

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ethylene dichloride (pH 2.5) extracted. The extract was 2 χ washed with 56 ml of water, then dried over magnesium sulfate, filtered and concentrated to a υΐ (io, 1 g). .

Las Cl vrardre in 34 ^rn l Athylenclichlorid dissolved, then 2.4 gd (+) -amphetamine were added in 16 ml ilthylendichlorid at .uaumtemperatur, stream was 3 hours. the i'estetoff formed is filtered off. I-ian received 2.25 g (56>: J yield) deo d- (+) -amphetamine salt from I ¹ . Ίο5-1ο7 ° 0, jp ^ CJ-Q = + 9.37 ° (c = 1, keüii).

Example 7

The output material according to Example 1 (11.3 g) was added xi.room temperature under lead dissolved in 79.3 ml "v / at-jser. Lay mixture was acidified with 0.1 ml of 6N hydrochloric acid and the so released öäux'e vmrde 4 x with 25 ml! -! ethylene- ■ Chloride extracted. The extract then vmrde 2 χ with 56.5 ml each Mostly extracted and dried over caustic soda sulphate.

■ "ο- *

71 ml of the above extract was concentrated to 6.18 g of an oil. The Cl was dissolved in 35 ml of ethylene dichloride at ambient temperature, then 2.47 g of (+) -amphetamine in 15 ml of ethylene dichloride was added together with 25 ml of ethylene chloride. The mixture was stirred at hardly any temperature for 10 minutes and then left to stand overnight (about 18 hours). The solution was cooled to 10 0, since the crude α (+) -amphetamine salt was filtered off and dried , kan received 2.6 g of product (65, i yield ⁵

(c = 1, o2, Keüii).

Product (65, i yield), h \ 1o1-1o5 ° C, /V.7 ^ ⁵ = + 7.99 °

When 1.2 g of the crude salt crystallized from iithylene dichloride / kethylene chloride (2: 1) 1.15 g of the pure

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l ·) -Αία phetaiain fold from Ir. 11o-112 ° (J, 5 <_7 _T) = + 11.34 ° (c = 1, o3 LeOn) erht-lton.

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Claims (5)

Claims soldering process for the decomposition of racemic 2- (2ß-Benzyldxymethy.l-3Qt, -hydroxy-4-cyclopeiiten-10 (-yl) -acetic acid in the optical antipodes, thereby gekenriieich.net that one that d (+) -Amphetamiiisas the oacid from iithylenedichlorid, dioxane, Ethylene dichloride / diethylene chloride or l'etramethylene dichloride / Ohloroi'orm crystallized fractionally for up to 2-18 hours and separating the resulting crystalline salt from the. 2. The method according to claim 1, characterized in that aas (+) -Arnpheta.min & alz in the optically active, free converts. 3. The method according to claim 1, characterized in that the crystallization is carried out at a concentration of 3 to 1ο _ν ό (weight / volume). 4. The method .nach claim 3, because: .by characterized in that the solution! .Mittel j'.tliylendichloria / hetliyl.enchlorid in a volume ratio of 2: 1 is used. 5. The method according to claim 3, characterized in that one the Lo.-ungi; riiittel Tetrainethylene dichloride / oleoroform im 2: 1 starts. .7'iir: j lizer Inc. He.w lork, Κ.Ϊ. ,, V., it.A. : I am vs the lawyer 3 0 9 8 17/1 13 1 BATH