DD235251A1 - METHOD FOR SEPARATING BETA BINAPHTHYL PHOSPHORIC ACID RAZEMATES - Google Patents

Abstract

The invention relates to a process for the separation of b-Binaphthylphosphorsaeure racemates of the formula A without the use of alkaloids, but using synthetic (1S: 2S) -2-amino-1- (4-nitrophenyl) -propandiol- (1, 3), the so-called L-base, or (1R: 2R) -2-amino-1- (4-nitrophenyl) -propandiol- (1,3), the so-called D-base, in the presence of a ketone ( such as acetone) or an aldehyde in a solvent (such as methanol or ethanol). When the water escapes, a salt-like 1: 1: 1 condensate (base / ketone / acid or base / aldehyde / acid) is formed. The enantiomers of Binaphthylphosphorsaeure are in turn suitable for racemate separation of biological agents and certain drugs.

Description

Field of application of the invention

The invention relates to a process for the separation of / 3-Binaphthylphosphorsäure-racemates of the general formula A, in which R can represent hydrogen, halogen, nitro or alkyl.

The atropisomeric / 3-binaphthylphosphoric acids, in turn, are useful for the racemate separation of biologically active agents and drugs, and can be used to prepare chiral / 3-binaphthols.

The field of application of the invention is primarily in the production of active ingredients in the chemical, especially in the pharmaceutical chemical industry.

Characteristic of the known technical solutions

It is known that / 3-Binaphthylphosphorsäuren and substituted derivatives with alkaloids, such as cinchonine and cinchonidine, can be cleaved into their enantiomers (see, patents CH 576921 [1971] and DE-OS 2212600 and J. Jacques, C. Fouquey uRViterbo Tetrahedron Lett., 48, 1971, 4617; J. Jacques et al., Enantiomers, Racemates and Resolutions, J. Wiley & Sons, 1981). The use of other alkaloids, such as brucine, quinine or morphine, as well as the use of optically active bases was likewise stimulated at the time (cf patent specifications CH 576921). It has also been suggested in this connection that both (1S: 2S) -2-amino-1- [4-nitrophenyl] -propanediol (1,3), the so-called L-base from the chloramphenicol synthesis, as well as (1R: 2R) -2-amino-1- [4-nitrophenyl] -propandiol- (1,3), the so-called D-base, for the racemate separation of chiral acids (see also J. Jacques et al. cit., 1981). Finally, it is also known that the o.g. Bases can condense with itself with ketones and aldehydes to heterocycles. The disadvantage of the known methods for separating / 3-binaphthylphosphoric acids is that the crystallization of the corresponding diastereoisomeric cinchonine or cinchonidine-β-binaphthylphosphoric acid salts proceeds slowly and the diastereoisomers are only partially separated. In addition, the alkaloids to be used in this case can be provided only with great effort in the required amounts. In addition, protective measures against the toxic effects of these substances should be provided for when they are used.

Finally, neither the above-mentioned L nor D base, as was found by us, taken by itself able to separate .beta. binaphthylphosphoric into their enantiomers as in alcohols such as in esters occurs as a solvent, no crystallization.

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Object of the invention

The object of the invention is to separate chiral / 3-binaphthylphosphoric acids into their enantiomers. Explanation of the essence of the invention

The invention has for its object to describe an improved method, according to the Razemate the chiral ß- Binaphthylphosphorsäure economically advantageous, can be separated quickly and in optical purity, without having to use alkaloids.

This object is achieved in accordance with the invention in that racemic / 3-Binaphthylphosphorsäure the general formula A with (1S: 2S) -2-amino-1- [4-nitro-phenyl] -propandiol- (1,3), hereinafter Called L-base, or with (1R: 2R) -2-amino-1- [4-nitro-phenyl] -propandiol- (1,3), hereinafter called D-base, in the presence of a carbonyl compound, ie an aliphatic or aromatic ketone or aldehyde or a mixed aliphatic-aromatic ketone, preferably in the presence of either acetone, ethyl methyl ketone, diethyl ketone or cyclohexanone or acetophenone or in the presence of benzaldehyde in an alcohol (such as methanol or ethanol) or in one Ester (such as ethyl acetate) is reacted with the sparingly soluble diastereoisomeric salt under water as 1: 1: 1 condensate (base / ketone / acid or base / aldehyde / acid), so for example as L-base / acetone / ( +) / 3-binaphthylphosphoric acid condensate. Condensation of the ketone or aldehyde with the optically active base used in each case produces the corresponding (optically active) substituted oxazolidines or 1,3-dioxanes or azomethines which are stereospecifically sparingly soluble with only one enantiomer of the / 3-binaphthylphosphoric acid racemate not recrystallizable without change) salts.

Surprisingly, the separation of / 3-Binaphthylphosphorsäure-racemates only after ketone or aldehyde addition and subsequent condensation reaction with the L or D base possible (while the salt formation of / 3-Binaphthylphosphorsäure and optically active base in turn, as stated above does not lead to crystalline diastereoisomer salt pairs).

The resulting saline 1: 1: 1 condensate is then cleaved by treatment with acid, preferably hydrochloric or acetic acid, to give optically active / 3-binaphthylphosphoric acid, i. depending on the optically active base used in each case either (+) - or (-) + - Binaphthylphosphorsäure, highly enriched in crystalline form, is deposited.

After repeated separation according to the method, the enantiomers of the / 3-binaphthylphosphoric acid A are finally obtained with specific rotations of [α] § ⁵ = + 611.8 ° (c = 0.0108 g / ml, MeOH) or -611.5 ° (c = 0.0094 g / ml, MeOH). In contrast, the rotations achieved with alkaloids (see J. Jaques et al., Tetrahedron Lett. 48, 1971, 4617) are significantly lower (Ja] If ₉ = + 530 °, c = 0.0135 g / ml, MeOH). , ie, in accordance with the procedure of the invention, the separation of / 3-Binaphthylphosphorsäure is achieved in their enantiomers in optical purity.

The separation into the enantiomers succeeds in the present process both when using racemic / 3-Binaphthylphosphorsäure as well as when using enriched, optically impure (+) - or (-) / 3-Binaphthylphosphorsäure (from the mother liquors of previous separation operations).

In its preferred embodiment, the method is still configured as follows:

Portions of 50g to 100g racemic-Binaphthy! Phosphoric acid and 10g to 50g L-resp. D-base are dissolved in 0.11 to 5% oil of an alcohol such as methanol in the heat, filtered, and 0.11 to 5.01 of a ketone such as acetone or an aldehyde such as benzaldehyde is added. The precipitated as a result of the reaction diastereoisomeric 1: 1: 1 condensate is filtered off with suction, then suspended with 0.11 to 1.0I water and mixed with 0.11 to 1.01 concentrated hydrochloric acid and heated to 95 ° C. As a result, 20 g to 45 g of highly enriched, i. optically active, (+) - or (-) / 3-Binaphthylphosphorsäure which is subjected to a new separation operation according to the method described above, but the acid and the base are not used in a ratio of 1: 1. This results in the end 10g to 40g of the respective optically pure enantiomer.

The advantages of the invention are seen in that

- In their application, the separation of racemic / 3-Binaphthylphosphorsäure A into their enantiomers in optical purity succeeds;

- This separation is now achievable in shorter times and can be carried out using less toxic and moreover relatively easier to access auxiliaries.

Exemplary embodiments;

The invention is illustrated by the following exemplary embodiments.

The final product in each example is optically pure (+) - or (-) / 3-binaphthylphosphoric acid. The headings characterize each of the diastereoisomeric, new 1: 1: 1 condensate, which arises as an intermediate.

example 1

L-base / acetone / (+) / 3-binaphthylphosphoric acid condensate (1 a) I. Separation

52.5 g (0.15 mol) of (±) / 3-binaphthylphosphoric acid, ie the substance of formula A with R = H, and 15.9 g (0.075 mol) of L-base are dissolved in 150 ml of methanol while hot, filtered and added 1.81 acetone. After about 20 minutes, the crystallization begins. After standing overnight in the refrigerator is aspirated. The yield is 37.9 g (90% of theory, based on one enantiomer) of colorless crystals of mp. 215 ⁰ C to 218 ⁰ C.

The diastereoisomeric salt (37.9 g) is suspended in 500 ml of water, 20 ml of conc. Hydrochloric acid added and heated to 95 ⁰ C. After cooling, the (+ (- enantiomer is filtered off with suction as a colorless crystal powder and dried at 110 ° C. The yield is 22.3 g (85% of theory) of colorless crystals (+) / 3-binaphthylphosphoric acid with a rotation value of [a ] _D ⁵ ° = 592.7 ° (c = 0.01 g / ml, methanol).

2.Trennung

22.3 g (0.064 mol) of (+) / 3-binaphthylphosphoric acid (Hd ⁵ = 592.7 °) and 13.6 g (0.064 mol) of L-base are dissolved in 80 ml of methanol while hot, filtered and 250 ml of acetone are added. After cooling is filtered off with suction.

C ₃₂ H ₂₉ N ₂ O ₈ P (600.6) mp 221 to 223 ° C

Ben: C = 64.00 Gef .: C = 63.75

H = 4.87 H = 5.07

N = 4.66 N = 4.76

35.9g SaIzIa be suspended in 400 ml of water, 20 ml of conc. Hydrochloric acid added and heated again to 95 ° C, cooled, filtered with suction and dried at 110 ⁰ C. The yield is 19.4 g (87% of theory) of colorless crystals of optically pure (+) / 3-binaphthylphosphoric acid with a rotation value of [α] "= + 611.8 ° (c = 0.0108 g / ml, methanol ).

Example 2 D-cheese / acetone / (-) / 3-binaphthylphosphoric acid condensate (1 b)

I.Trennung

10.44 g (0.03 mol) / 3-binaphthylphosphoric acid (from the methanol / acetone filtrates of the L-base cleavages, [a] § ⁵ about -300 °) and 6.36 g (0.03 mol) (D-). Base) are dissolved in 50 ml of methanol in the heat, filtered and added 200 ml of acetone. After 15 minutes 1 b crystallizes out. After standing for three hours in the refrigerator, about 13.9 g of colorless crystals can be removed by suction. The melting range is 224 to 226 ° C. The recrystallization is not possible without decomposition.

The salt is suspended in 150 ml of water, concentrated with 4 ml. Hydrochloric acid and heated to 95 ° C. After cooling and suction, it is dried at 110.degree. This results in 7.7 G (-) ß-Binaphthylphosphorsäure; [α] "= -614.5 ° (c = 0.01 g / ml, methanol).

2nd separation

7.5 g (0.0216 mol) of (-) / 3-binaphthylphosphoric acid and 4.6 g (0.0216 mol) of D-base are dissolved in 25 ml of methanol in the heat and treated with 80 ml of acetone. 1b separates. After filtration, cooling and suction, 12.1 g of colorless crystals with a melting range of 221 to 223 ° C. are obtained.

C ₃₂ H ₂₉ N ₂ O ₈ P (600.6)

Calc .: C = 64.00 Gef .: C = 63.79

H = 4.87 H = 5.18

N = 4.66 N = 4.40

10 g of the salt are suspended in 120 ml of water and concentrated with 6 ml. Hydrochloric acid heated to 95 ⁰ C, cooled and filtered off with suction optically pure (-) / 3-Binaphthylphosphorsäure and dried at 110 °. 5.9 g yield, [o.] Q ⁵⁰ = 611.5 ° (c = 0.0094 g / ml, methanol).

Example 3

L-base / methylethylketone / (+) / 3-binaphthylphosphoric acid condensate (2a) 1.7g (5mmol) highly enriched (+) beta-binaphthylphosphoric acid and 1.1g (5mmol) L-base are dissolved in 20ml acetic acid and 5ml abs. Ethanol heated to dissolve and added 3.6 g (50 mmol) of methyl ethyl ketone. After a few hours in the refrigerator 2a crystallizes out. Yield 2.35 g of colorless crystals, melting range 223 to 225 ° C.

C ₃₃ H ₃ IN ₂ O ₃ P (614.8)

Calc .: C = 64.49 Gef .: C = 64.81

H = 5.08 H = 5.06

N = 4.56 N = 4.58

The diastereoisomeric salt is decomposed with hydrochloric acid and optically pure (+) / 3-binaphthylphosphoric acid separated. Example 4

D-base / methyl ethyl ketone / (-) / 3-binaphthylphosphoric acid condensate (2 b) 1.7g (5mmol) highly enriched (-) / 3-binaphthylphosphoric acid and 1.1g (5mmol) D-base are dissolved in 20ml ethyl acetate and 5ml abs. Ethanol heated to dissolve and added 3.6g (50mmol) of methyl ethyl ketone. After a few hours in the refrigerator crystallization begins. Total yield after evaporation of the filtrate 2.3 g of colorless crystals 2b of the melting range 218 to 220 ° C.

C ₃₃ H ₃₁ N ₂ O ₈ P (614.8)

Calc .: C = 64.49 Gef .: C = 63.67

H = 5.08 H = 4.94

N = 4.56 N = 4.52

The diastereoisomeric salt is decomposed with hydrochloric acid and optically pure (-) / 3-Binaphthylphosphorsäure separated.

Example 5

L-base / diethyl ketone / (+) / 3-binaphthylphosphoric acid condensate (3a) 1.7g (5mmol) highly enriched (+) / 3-binaphthylphosphoric acid and 1.1g (5mmol) L-base are dissolved in a mixture of 20ml ethyl acetate and 5ml abs. Ethanol heated to dissolve and 4.3 g (50 mmol) of diethyl ketone added. After about 3 hours, the crystallization begins. After standing in the refrigerator is filtered off with suction, washed with ethyl acetate, the filtrate was evaporated and the residue brought to crystallization with addition of ethyl acetate and diethyl ketone. Yield 2.3 g colorless crystals 3a, melting range 212 to

C ₃₄ H ₃₃ N ₂ O ₈ P (614.6)

Calc .: C = 64.96 Found: C = 63.65

H = 5.29 H = 5.19

N = 4.46 N = 3.91

The diastereoisomeric salt is decomposed with hydrochloric acid and optically pure (+) / 3-binaphthylphosphoric acid separated. Example 6

D-base / diethyl ketone / (-) / 3-binaphthylphosphoric acid condensate (3b) 1.7g (5mmol) (-) / 3-binaphthylphosphoric acid and 1.1g (5mmol) D-base are dissolved in a mixture of 20ml ethyl acetate and 5ml Section. Ethanol until dissolved and added 4.3 g (5 mmol) of diethyl ketone. After about 2 hours, the crystallization begins. It is suctioned off, washed with ethyl acetate and further crystals from the filtrate. Yield 2.3 g of colorless crystals 3 b of the melting range 213 to 215 ° C.

-4- 739

C ₃₄ H ₃₃ N ₂ O ₈ P (614.6)

Calc .: C = 64.96 Found: C = 64.46

H = 5.29 H = 5.50

N = 4.49 N = 4.24

The diastereoisomeric salt is decomposed with hydrochloric acid and optically pure (-) / 3-Binaphthylphosphorsäure separated.

Example 7

L-base / cyclohexanone / f + iβ-binaphthylphosphoric acid condensate (4a) 1.7 g (5 mmol) of (+) / 3-binaphthylphosphoric acid and 1.1 g (5 mmol) of L-base are dissolved in a mixture of 20 ml of ethyl acetate and 5 ml abs.

Dissolved ethanol in the heat and added 4.9 g (50 mmol) of cyclohexanone. After about 1 hour, the crystallization begins. After standing overnight in the refrigerator, it extracts more crystals from the mother liquor and receives 2.9 g of colorless crystals 4a of melting range 243-244 ° C.

C ₃₅ H ₃₃ N ₂ O ₈ P (640.6)

Calc .: C = 65.62 Found: C = 65.74

H = 5.19 H = 5.75

N = 4.37 N = 4.17

The diastereoisomeric salt 4a is decomposed with hydrochloric acid and optically pure (+) / 3-binaphthylphosphoric acid separated. Example 8

D-base / cyclohexanone / f-isl-binaphthylphosphoric acid condensate (4b) 1.7 g (5 mmol) of (-) / 3-binaphthylphosphoric acid and 1.1 g (5 mmol) of D-base are dissolved in a mixture of 20 ml of ethyl acetate and 5 ml Section. Ethanol dissolved in the heat and added 4.9 g (50 mmol) of cyclohexanone. It is allowed to stand overnight in the refrigerator, filtered off with suction, washed with ethyl acetate and recovered after evaporation of the filtrate more crystals 4b. Yield 2.9 g of colorless crystals with melting point 243 to 244 ° C.

C ₃₅ H ₃₃ N ₂ O ₈ P (640.6)

Calc .: C = 65.62 Found: C = 65.69

H = 5.19 H = 5.21

N = 4.37 N = 4.46

The diastereoisomeric salt 4b is decomposed with hydrochloric acid and optically pure (-) / 3-binaphthylphosphoric acid separated.

Claims (7)

-1- 739 Invention claim: 1. A process for the separation of / 3-binaphthylphosphoric acid racemates of general formula A, in which R can denote hydrogen, halogen, nitro or alkyl, characterized in that Racemic / 3-binaphthylphosphoric acid reacted with L-base or D-base in the presence of a carbonyl compound in an alcohol or ester, - The resulting diastereoisomeric salt-like 1: 1: 1 condensate then cleaved by treatment with acid and - Optically active after the first race) +) - or (-) / 3-Binaphthylphosphorsäure and after the second separation optically pure (+) - or (-) / 3-Binaphthylphosphorsäure deposited in crystalline form 2. The method according to item 1, characterized in that τ- portions of 50g to 100g racemic acid-Binaphthylphosphorsäure and 10g to 50g L-resp. D-base dissolved in 0.1 l to 5.01 of an alcohol in the heat and, after filtration, 0.11 to 5.01 of a carbonyl compound are added and - Suctioned the resulting diastereoisomeric 1: 1: 1 condensate as a result of the reaction, then suspended with 0.11 to 1.01 water and treated with 0.11 to 1.01 concentrated hydrochloric acid or acetic acid for the purpose of its cleavage. 3. The method according to item 2, characterized in that methanol is used as the alcohol. 4. The method according to item 2, characterized in that an aliphatic, an aromatic or a mixed aliphatic-aromatic ketone is used as the carbonyl compound. 5. The method according to item 4, characterized in that is used as the ketone either acetone, ethyl methyl ketone, diethyl ketone, cyclohexanone or acetophenone. 6. The method according to item 2, characterized in that an aliphatic or an aromatic aldehyde is used as the carbonyl compound. 7. The method according to item 6, characterized in that benzaldehyde is used as the aldehyde.