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Crystalline salts of (z)-o-octadec-9-en-1-yl o,o-dihydrogen phosphorothioate

a technology of dihydrogen phosphorothioate and crystalline salts, which is applied in the field of crystalline and/or semicrystalline salts of (z) — ooctadec9en1yl o, odihydrogen phosphorothioate, can solve the problems of poor water solubility, difficult to handle for practical purposes, and failure to yield filterable solids in attempts to form more desirable salt forms such as sodium or potassium salts

Inactive Publication Date: 2017-08-10
RXBIO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is related to methods for producing certain compounds. One method involves mixing a certain amino acid with a certain solvent, and allowing the resulting mixture to form crystalline salts. The solvent can be a combination of methanol and water, or other solvents like methanol alone or a mixture of methanol and IPA. After the crystalline salts are formed, the solvent is removed and the resulting material is dried. Another method involves mixing a different amino acid with another solvent, and allowing the mixture to form crystalline salts. These crystalline salts can then be used to produce a specific compound by carrying out a hydrolysis reaction. The present invention provides new methods for producing certain compounds, which can be useful in various applications.

Problems solved by technology

In addition to being in a less desirable oil form it has a thiol type odor, needs storage at less than −20° C. to preserve short-term stability, has poor solubility in water, and is difficult to handle for practical purposes.
Attempts to form more desirable salt forms such as the sodium or potassium salts failed to yield filterable solids.
However, Rx100.Ammonia salt also has many undesirable features.

Method used

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  • Crystalline salts of (z)-o-octadec-9-en-1-yl o,o-dihydrogen phosphorothioate
  • Crystalline salts of (z)-o-octadec-9-en-1-yl o,o-dihydrogen phosphorothioate
  • Crystalline salts of (z)-o-octadec-9-en-1-yl o,o-dihydrogen phosphorothioate

Examples

Experimental program
Comparison scheme
Effect test

example 1

Medicinal Chemistry Route of Synthesis for Rx100.FA

[0126]The prior procedure for making Rx100.FA involved phosphorylation of oleyl alcohol with bis(cyanoethyl)-N,N-diisopropylphosphoramidite in the presence of tetrazole followed by sulfurization with elemental sulfur. Protecting groups were then removed by (3-elimination upon treatment with methanolic potassium hydroxide. After acidic work-up, Rx100.FA was isolated as a pale yellow oil. See the scheme I in FIG. 36.

[0127]1.1 Synthetic Approaches with Protective Groups and a Scheme I

[0128]The prior medicinal chemistry approach (Scheme I in FIG. 36) for the synthesis of Rx100.FA utilized 1H-tetrazole which is explosive and is not easily amenable to scale-up. We evaluated other activators to replace problematic 1H-tetrazole. We considered four alternatives for this purpose. They were 4, 5-Dicyanoimidazole (DCI) with N-methyl imidazole (NMI); 5-Benzylthio-1H-tetrazole; Pyridinium trifluoroacetate with NMI and 5-Ethyl thio-1H-tetrazole.

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example 2

ation and Crystallization of the Rx100.L-Lysine Salt

[0141]We previously isolated an Rx100.Ammonia salt via freeze-drying of a suspension of Rx100-free acid in methanolic ammonia. See the Scheme III in FIG. 38. As explained in the Background section, the ammonia salt is less desirable and a new salt form is sought after as described in this Example 2.

[0142]2.1 Screening for Rx100 Crystalline Salts.

[0143]We designed a complex and unconventional screening regime to screen for Rx100 crystalline salts. The most viable Rx100 salts were chosen for further characterization based on crystallinity, filterability, stability at high humidity and polymorphic behavior. The screening regime is described as follows.

TABLE 4List of bases and their corresponding number.SolutionBaseExperimentconcentration,numberStageBase nameBase was prepared inwt %1Stage 1Sodium hydroxideWater9.72Ammonium hydroxideWater10.23EthylenediamineN / A99.04DiethylamineN / A99.05Tromethamine (Tris)Water10.06Hydroxyethyl morpholine...

example 3

evelopment

[0177]3.1 Evaluation of the Process Variables that were Suspected to Influence the Quantity of Impurities in the Two Step Synthesis and Purification of Rx100.FA.

[0178]We evaluated the process variables that were suspected to influence the quantity of impurities in the two step synthesis and purification of Rx100.FA in Scheme III FIG. 38. This study was performed at 5 g batch synthesis. The variable process factors were reaction temperature in reaction Step 1, and the stoichiometry of triethylamine and sodium hydroxide used in reaction Step 2. In step 1, the union of pyridine and thiophosphoryl chloride prior to the addition of cis-oleyl alcohol produces a heterogeneous solution which upon stirring turns clear. The length of time it takes the solution to turn clear was suspected to be temperature dependent, but to vary this factor and include it in the study design would dramatically increase the number of runs so we waited until the solution turned clear (a process control...

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Abstract

Here provided are a salt of Z)—O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate with an L-lysine addition in crystalline form and methods of making and using the same.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 14 / 569,383, filed Dec. 12, 2014, which in turn claims the benefit of priority of earlier-filed U.S. Provisional Patent Application Nos. 61 / 921,938, filed on Dec. 30, 2013, the disclosure of which applications are incorporated herein by reference.GOVERNMENTAL SUPPORT[0002]The research is partly supported by a government grant from the Biomedical Advanced Research and Development Authority (BARDA), within the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (grant#HHSO100201100036C).FIELD OF INVENTION[0003]The present invention relates to crystalline and / or semi-crystalline salts of (Z)—O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate, and methods of making and using the crystalline and / or semi-crystalline salts.BACKGROUND[0004]The compound (Z)—O-octadec-9-en-1-yl O,O-dihydrogen phosphorothioate (herea...

Claims

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Application Information

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IPC IPC(8): C07F9/06C07C229/26
CPCC07F9/062C07B2200/13C07C229/26C07F9/205C07F9/206C07F9/2408C07F9/203
Inventor SINGIDI, RAMA KRISHNA REDDYGUDUDURU, VEERESHMIRMEHRABI, MAHMOUDTHOMPSON, KARIN EMMONSTIGYI, GABOR JOZSEFYATES, CHARLES RYANSTROBOS, JURRIAAN
Owner RXBIO