Method for chiral restructuring of norketamine

Abstract

This disclosure relates to (2R,6R)-hydroxynorketamine (HNK) and (2S, This invention provides a method for synthesizing the free base form of 6S)-hydroxynorketamine. [Solution] In one embodiment, (2R,6R)-hydroxynorketamine (HNK The synthesis of ) is via chiral resolution using L-pyroglutamic acid, which is used to synthesize raceminolketamine. This disclosure includes preparing (R)-norketamine by chiral restructuring. Furthermore, the corresponding (2R,6R)-hydroxynorketamine (HNK) and (2S,6S) - Provides the crystalline form of hydroxynorketamine hydrochloride.

Claims

1. (2R,6R)-hydroxy, characterized by single crystal parameters approximately equal to those of the following: Crystallographic form of norketamine hydrochloride. a = 7.35 Å, alpha = 90° b = 7.49 Å, beta = 96.87° c = 11.35 Å, gamma = 90° V=621.02Å ３ Grid dimensions including, and Space group = P 1 21 1, Crystal system = Monoclinic, Molecules per unit cell = 1, Density ( Calculated value) = 1.477 mg / m² ３

2. The crystal morphology according to claim 1, wherein a detectable amount determined by X-ray powder diffraction It must not contain any other crystalline form of hydroxynorketamine or hydroxynorketamine salts. A crystal form characterized by the following.

3. (2S,6S)-hydroxy, characterized by single crystal parameters approximately equal to those of the following: Crystallographic form of norketamine hydrochloride. a = 7.35 Å, alpha = 90° b = 7.48 Å, beta = 96.87° c = 11.34 Å, gamma = 90° V=619.32Å ３ Grid dimensions including, and Space group = P 1 21 1, Crystal system = Monoclinic, Molecules per unit cell = 1, Density ( Calculated value) = 1.481 Mg / m³ ３

4. The crystal morphology according to claim 3, wherein a detectable amount determined by X-ray powder diffraction It must not contain any other crystalline form of hydroxynorketamine or hydroxynorketamine salts. A crystal form characterized by the following.

5. A method for chiral resolution of norketamine, comprising (D)-(R)-pyroglutamine The acid was added to raceminorketamine in a solvent, and the solid (S)-norketamine D-pyroglutame A method characterized by comprising forming a tide.

6. The method according to claim 5, wherein the (S)-norketamine D-pyroglutamate is ( A method characterized by further comprising converting to S)-norketamine.

7. A method for chiral resolution of norketamine, comprising (L)-(S)-pyroglutamine An acid is added to raceminorketamine in a solvent to form a solid (R)-norketamine L-pyroglutame. To form a tide, and (R)-norketamine L-pyroglutamate to (R)-norketamine L-pyroglutamate A method characterized by including conversion to ketamine.

8. (2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine A method for producing tamins or salts thereof, 【Chemistry 1】 Equation Ia 【Chemistry 2】 Formula Ib The compound of formula Ia or formula Ib is used with a base, then with a trialkylsilyl chloride, then with a pe Formula Ia was treated with a luoxy compound, and then optionally with an acid or fluoride source. In this case, the compound of formula IIa is obtained, or if formula Ib is treated, the compound of formula IIb is obtained. That is, the compound of formula IIa or formula IIb contains a carbamate bond, 【Transformation 3】 Formula IIa 【Chemistry 4】 Equation IIb and The carbamate bond of the compound of formula IIa or formula IIb is cleaved, and the formula II When the carbamate bond of compound a is cleaved, (2R,6R)-hydroxynor When the carbamate bond of ketamine or the compound of formula IIb is cleaved, (2 To obtain S,6S)-hydroxynorketamine and 【Transformation 5】 (2R,6R)-hydroxynorketamine 【Transformation 6】 (2S,6S)-hydroxynorketamine; (wherein, R １ is C １ - C ６ alkyl, C １ - C ６ haloalkyl, benzyl, 4-methoxy (It is benzyl or 2-trimethylsilylethyl.) A method characterized by including the following.

9. The method according to claim 8, R １ However, it is tert-butyl, and the carbamate Breaking the bond includes treating the compound of formula IIa or formula IIb with an acid. A method characterized by the following:

10. The method according to claim 9, characterized in that the acid is trifluoroacetic acid. method.

11. The method according to claim 8, wherein (2R,6R)-hydroxynorketamine is treated with hydrochloric acid To process and produce (2R,6R)-hydroxynorketamine hydrochloride, or (2S (2S,6S)-hydroxynorketamine is treated with hydrochloric acid to obtain (2S,6S)-hydroxynorketamine. A method characterized by further comprising the production of ketamine hydrochloride.

12. A method according to claim 8, wherein the compound of formula Ia or formula Ib is used A method characterized in that the base used is a strong base.

13. The method according to claim 12, wherein the strong base is diisopropylamide lithium, Sodium hexamethyldisilazane, potassium hexamethyldisilazane, or sec- It is lithium, and the compound of formula Ia or formula Ib is at a temperature below 0°C, the strong salt A method characterized by being processed by a base.

14. A method according to claim 8, wherein the compound of formula Ia or formula Ib is treated with a base. The compound of formula Ia or formula Ib is subjected to diisopropyl ammonium compounds at a temperature below -50°C. A method characterized by including treatment with tritium.

15. A method according to any one of claims 8 to 14, wherein the trialkylsilyl chloride The substances are trimethylsilyl chloride, triethylsilyl chloride, and tert-butyldimethylsilyl chloride. A method characterized by using lyl chloride or triisopropylsilyl chloride.

16. The method according to claim 15, wherein the trialkylsilyl chloride is trimethylsilyl A method characterized by being a chloride.

17. A method according to any one of claims 8 to 16, wherein the peroxy compound is peroxy compound A method characterized by using luoxy acid or a peroxide.

18. The method according to claim 17, wherein the peroxy compound is meta-chloroperoxy Benzoic acid, peroxybenzoic acid, peracetic acid, dimethyldioxirane, tert-butylhydride A method characterized by using a peroxide or hydrogen peroxide.

19. A method according to any one of claims 8 to 18, wherein treatment with the peroxy compound. After that, the compound of formula Ia or formula Ib is converted with tetra-n-butylammonium fluoride. A method characterized by being processed.

20. A method according to any one of claims 8 to 19, wherein the peroxy compound is A method characterized by using ter-chloroperoxybenzoic acid.

21. A method according to any one of claims 8 to 20, wherein (R)-norketamine is (R １ O ２ C) ２ O or R １ O ２ To react with C-X to produce the compound of formula Ia, Alternatively, (S)-norketamine (R １ O ２ C) ２ O or R １ O ２ React with C-X By generating the compound of formula Ib, the compound of formula Ia or formula Ib is generated. A method characterized by further comprising the action of (wherein X is a halogen).

22. The method according to claim 21, R １ However, it is tert-butyl, and the chemical formula Ia above The compound is formed by (R)-norketamine (tert-butyl-O ２ C) ２ O and opposite This includes causing the compound of formula Ib to respond, and producing (S)-norketamine ( tert-butyl-O ２ C) ２ A method characterized by including a reaction with O.

23. The method according to claim 8, 【Transformation 7】 Equation Ia The compound of formula Ia is subjected to diisopropylamide lithium at a temperature below -50°C, and then Trimethylsilyl chloride, then meta-chloroperoxybenzoic acid, then fluoride Treatment with trans-n-butylammonium yields the compound of formula IIa (wherein R １ (It is tert-butyl.) 【Transformation 8】 Formula IIa and The carbamate bond in formula IIa is cleaved by treatment with acid, (2R, 6R ) - Obtaining hydroxynorketamine and 【Chemistry 9】 ((2R,6R)-hydroxynorketamine) A method characterized by including the following.

24. The method according to claim 8, 【Chemistry 10】 Formula Ib The compound of formula Ib is subjected to diisopropylamide lithium at a temperature below -50°C. First, trimethylsilyl chloride, then meta-chloroperoxybenzoic acid, then fluoride Treatment with tetra-n-butylammonium to obtain the compound of formula IIb (wherein, R １ (It is tert-butyl.) 【Chemistry 11】 Equation IIb and The carbamate bond in formula IIb is cleaved by acid treatment, resulting in (2S, 6S ) - Obtaining hydroxynorketamine and 【Chemistry 12】 ((2S,6S)-hydroxynorketamine) A method characterized by including the following.

25. At least five, at least eight, at least ten of the following (2θ) values, This shows the XRPD spectrum of characteristic peaks in at least 12 arbitrary combinations. A characteristic feature is the crystalline form of (2R,6R)-hydroxynorketamine. １２．１、１３．６、１４．１、１５．１、１５．６、１６．９、１８．０、１９．２ 、１９．５、２０．８、２２．１、２３．５、２４．０、２４．３、２４．６、２４．８ 、２５．２、２６．４、２７．０、２７．４、２７．７、２８．１、２９．９、３０．２ 、３１．５、３１．９、３２．４、３２．７、３３．５、３４．７、３６．５、３７．１ , 37.7, 38.3, 38.7, 39.1, and 39.6

26. (2R, 6R) ) - The crystalline form of hydroxynorketamine.

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