US20190161493A1 - Novel harringtonines salts in the crystalline state, their use for the purification of the corresponding drug substance and as chemotherapeutic agents given alone or combined with radiotherapy or as immunomodulating agents - Google Patents

Abstract

The invention also relates to a process for preparing and purifying these salts and their use as chemostherapeutic drugs, alone or combined with radiotherapy, or as immunomodulating agents.

Description

• The present invention concerns crystalline salts of harringtonines, protonated on their alkaloid nitrogen, definite by their solid state analysis patterns, their process of preparation allowing their use as drug substance for blending alone or in combination in pharmaceutical composition useful as chemotherapeutic agents, given alone or combined with radiotherapy, or useful for treating parasitic and viral diseases and/or as immunomodulating agents, particularly in using oral or parenteral modes of administration.
• Among harringtonines, homoharringtonine (=HHT, named omacetaxine D.C.I. as drug substance) is a natural ester of cephalotaxine (see scheme 1 and table 1), an alkaloid of Cephalotaxus harringtonia, a rare and endangered Asian conifer belonging to the Cephalotaxaceae family. HHT content in renewable parts of Cephalotaxus is about a few dozen of mg only per kilo of dry plant material. This characteristic, in despite of considerable efforts performed by the U.S. National Cancer Institute, hampered clinical development of omacetaxine for more than thirty-years. On March 1998, the discovering of a new hemi-synthetic process by the Applicant, allowed industrial production of homoharringtonine at the kilo scale (U.S. Pat. No. 6,831,180 and Robin et al. Tet. Lett. 1999. p.2931)] and divided by 70 the need of rare plant material (Nicolini et al., Leukemia Research, 2014, 38, p.11545).
• Important Note:
• It should be noted that chemical structure of hemi-synthetic omacetaxine is strictly identical to the natural one version: omacetaxine is not a semi-synthetic derivative as indicated in some article published in literature (see scheme 1 and table 1). All denominations of omacetaxine (OMA) or homoharringtonine (HHT) included in this document are strictly equivalent regarding molecular structure. The sentence “omacetaxine is a semi-synthetic derivative of cephalotaxine” encountered in literature, is totally devoid of scientific significance: the semi-synthetic appellation suggests that a moiety of the molecule (cephalotaxine) would natural and that the other moiety (the side chain) would be unnatural (man designed) while the latter is strictly natural. When only a portion of a molecule was produced by synthesis, the process name is hemi-synthesis and the molecule is sometimes also called hemi-synthetic.
• Short History of Recent Development of Homoharringtonine.
• Initially, all above esters of cephalotaxine were discovered by U.S. teams (Powel et al., J. Pharm. Sc., 1972, 61, p.1227) and a large development program was performed by the United States National Cancer Institute (Suffness et al., J. Nat. Cancer Inst., 1988, 80, p.1095). In October 2012, the United States Food and Drug Administration (FDA) granted accelerated approval for omacetaxine mepesuccinate for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) who failed to respond to two or more tyrosine kinase inhibitors (TKIs) [ref fda]. Since this approval, hundreds of articles or reviews related to OMA/HHT were published in literature (more than 400 articles listed in SciFinder database). Definitive approval of OMA was granted in 2014 (Alvandi et al., The Oncologist, 2014, 19, p 94). This occurred after a very long and tumultuous period of clinical development (Kantarjian et al., Clin. Lymph. Myel. Leuk. 2013 p. 530), including early clinical development of HHT and, to a lesser extent, its congeners harringtonine (HA) and deoxyharringtonine (DHA) in various institution in the U.S. and in China. Finally, the successive involvement of seven pharmaceutical companies (Vivorex/American Bioscience; Oncopharm; Stragen; Chemgenex; Cephalon; TEVA) dispatched in 5 countries occurred before approval of omacetaxine! More than 50 clinical trials in USA, China and France involving more than 2000 patients.
• Definition (See Scheme 1 and Table 1)
• Homohamingtonine/Omacetaxine Mepesuccinate/Synribo/Myelostat
• The INN (Intemational Non-proprietary Name) “omacetaxine mepesuccinate” (OMA) is a name reserved for homoharringtonine HHT drug substance dedicated for pharmaceutical and medicinal use regardless its natural, hemi-synthetic or synthetic origin [formely named homoharringtonine]. Synribo (TEVA) and Myelostat (Oncopharm corporation) are trademark (F-D-C Reports, Pharmaceutical Approvals Monthly, 2001, 6, p.35).
• Cephalotaxanes Including Numbering
• Cephalotaxanes are particular alkaloids to date exclusively extracted from the Cephalotaxaceae family which exhibit the structural formula 1. Several substituants may be encountered on this core structure: hydroxyl, ether, acyloxy etc. The eventual presence of some additional double bound or intramolecular bridge achieve to definite cephalotaxanes. Cephalotaxines 2 are cephalotaxanes without acyloxy side-chain.
• Cephalotaxine 2a and drupacine 2b are example of cephalotaxines. Harringtonines 5 are particular cephalotaxanes formed by attachment of a branched α-hydroxyacyloxy side-chain at the 3-position of various cephalotaxines moieties. Cephalotaxines 2 and harringtonines 5, are examples of cephalotaxanes. Several dozen of cephalotaxanes have been isolated from various Cephalotaxus species. 4 is the generic formula of cephalotaxine esters (Takano et al., Phytochemistry, 1997, 44, p. 735 and cited references).
• Harringtonines 5 (i. e. harringtonine=HA and homoharringtonine=HHT) are particular cephalotaxine esters. Cephalotaxine and its natural ester are gathered under the generic term of cephalotaxane.
• Harringtoids are semi-synthetic derivatives of harrintonines.
• Harringtonic acids are side-chain of harringtonines.

• TABLE 1
  NATURAL AND SEMI-SYNTHETIC ESTERS OF CEPHALOTAXINE

  #	Trivial name	R2	R3	R4	Note #	Activity*
  5a	harringtonine	(CH3)2COH—(CH2)2—	Me	H	(1)	anticancer
  5b	homoharringtonine	(CH3)2COH—(CH2)3—	Me	H	(2)	anticancer
  5c	norharringtonine	(CH3)2COH—CH2—	Me	H	(3)	none
  5d	deoxyharringtonine	(CH3)2CH—(CH2)2—	Me	H	(4)	anticancer
  5e	bishomoharringtonine	(CH3)2COH—(CH2)4—	Me	H	(5)	none
  5f	isoharringtonine	(CH3)2CH(CH2)2—	Me	OH	(6)	none
  5g	neoharringtonine	C6H5—CH2—	Me	H	(7)	cytotoxic
  5h	harringtonines	R2—	Me	R4	(8)	N/A
  5i	harringtoids	R2—	R3	R4	(9)	cytotoxic

• (1) The first cephatotaxine ester isolated from oephalotaxus harringtonia *In cancer area, for definition of term see [Suffness et al in Journal of Natural Products 1982 p 1 Current Status of the NCI Plant and Animal Product Program] CYTOTOXICITY is toxicity to tumor cells in culture; ANTITUMOR is in vivo activity in experimental systems; ANTINEOPLASTIC or ANTICANCER are the reserved terms for reported clinical trials data.
• (2) “Homo” means one more carbon than harringtonine; Named omacetaxine (D.C.I.) as active pharmaceutical ingredient
• (3) “nor” means one more less carbon.
• 

  
• Two haringtonines are very promising drugs in the treatment of certain leukemia such as Chronic Myelogenous Leukemia (CML). Both homoharringtonine and harringtonine were used in human chemotherapy of leukemia for 30 years (see above Suffness et al.) and a large number of semi-synthetic analogs such as 5 on scheme 1 were synthesized (see “5.2 Cephalotaxus Esters With Side Chain Analogs” in above cited reference of Dumas et al.).
• Surprisingly, never crystalline salts of harringtonines have been isolated and described in literature.
• However, in spite of the progress recorded in production, purification and therapeutic use of homoharringtonine, several disadvantages persist:
• i) The cost of treatment for omacetaxine (Synribo) is prohibitive: $28,000 for induction, $14,000 for monthly treatments), this give about 180.000 $ per year, per patient [Kantarjian et al. Journal of Clinical Oncology, 2013, p3600; Hagop Kantarjian, personal communication]
• ii) The use of the parenteral route of administration even retards the development of this drug
• iii) Preparation of formulations for parenteral use is complicated by the use of lyophilization
• iv) Formation of non-crystalline salts of harrintonines give not as accurately defined compound as crystalline salts
• v) There is some local intolerance to this product when administered subcutaneously
• vi) On the other hand, although it has been known for almost 40 years, there is still a slight doubt regarding the absolute configuration of this series of natural product.
• Recent Scientific Discovering Regarding Mechanism of Activity of Harringtonines
• The team of Steitz (Journal of Molecular Biology 2009, 389, p. 146) recently demonstrated that homoharringtonine when in place in its active site was protonated in a neutral media, implying that alkaloid nitrogen protonation is imperative condition for the manifestation of the activity of this ligand.
• In addition, the team of Takano et al [J. Org. Chem. 1997 p. 8251) demonstrated experimentally that when the nitrogen lone pair of homoharringtonine was occupied by an oxygen atom, the cytotoxic activity was divided by a factor of at least 50. The authors conclude that “the nitrogen lone pair on the cephalotaxine skeleton appears to be essential for its activity”.
• The above mentioned team of Steitz showed that the absolute configuration of homoharringtonine deposited in the Cambridge Structural Database seems to be the opposite of that commonly adopted in the literature.
• The present invention relates to overcome the problems mentioned above. It also demonstrated that the absolute configuration in the deposited homoharringtonine Cambridge Structural Database seems to be the opposite of that commonly retained in the literature.
• The eight example of single crystal X-ray diffraction of homoharringtonine salt exhibited in FIGS. 2.3.1, 2.4.1, 2.5.1, 2.6.1, 2.8.1, 2.9.1, 2.11.1 and 2.12.1 clearly indicates that the alkaloid moiety was efficiently protonated by the processes described in the present invention. Moreover, the shortest distance between said proton carried by the nitrogen is close to two angstroms, showing the reality of the formation of a salt and not a mere co-crystal.
• 
• The present invention relates to overcome the problems mentioned above, namely:
• • raise doubt on the absolute configuration of harringtonines
  • provide a method of administration of harringtonines protonated on their nitrogen atom
• As detailed above, the fact that the real active form of harringtonines would be their nitrogen-protonated version was recently supported by the above cited works of Seitz et al. and Takano et al.
• The present invention concerns novel water soluble crystalline salts of homoharringtonine and their use as new chemical entities for the formulation of new cancer chemotherapeutic, or immunomodulating or antiparasitic agents and to implement new processes for purification including enantiomeric and determine the absolute configuration of the series.
• The present invention describes the preparation of crystalline salts of harringtonines as nitrogen-protonated form, stable and soluble in water and their use for the manufacture of pharmaceutical composition useful in the treatment of cancers, leukemias, immune disease and as reversal agents.
• The present invention describes an unambiguously proved method of protonation of harringtonine nitrogen.
• The present invention provides salts of harringtonines in the crystalline state, protonated on their alkaloid nitrogen, definite by their solid state analysis patterns, their process of preparation from harringtonines and commercial organic acid allowing their use as drug substance for blending alone or in combination with other chemotherapeutic agents such as, but not limited to, cytarabine or interferon or imatinib mesylate or dasatinib or arsenic trioxide or all-trans-retinoic acid, in a pharmaceutical composition particularly useful for treatment of cancer, alone or combined with radiotherapy, in using oral or parental modes of administration.
BRIEF DESCRIPTION OF DRAWINGS
• FIG. 1.1 is infra-red (IR) spectrum of Homoharringtonine (base alkaloid). FIG. 1.1 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.1 (ii) is IR(ATR) spectrum in the amorphous state.
• FIG. 1.2 is infra-red (IR) spectrum of Homoharringtonine hydrogen (S)-malate in the solid state. FIG. 1.2 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.2 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.3 is infra-red (IR) spectrum of Homoharringtonine hydrogen (R)-malate in the solid state. FIG. 1.3 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.3 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.4 is infra-red (IR) spectrum of Homoharringtonine hydrogen (2S, 3S)-tartrate in the solid state. FIG. 1.4 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.4 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.5 is infra-red (IR) spectrum of Homoharringtonine hydrogen (2R, 3R)-tartrate in the solid state. FIG. 1.5 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.5 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.6 is infra-red (IR) spectrum of Homoharringtonine hydrogen (2′″S)-citramalate in the solid state. FIG. 1.6 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.6 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.7 is infra-red (IR) spectrum of Homoharringtonine hydrogen (2′″R)-citramalate in the solid state. FIG. 1.7 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.7 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.8 is infra-red (IR) spectrum of Homoharringtonine succinate. FIG. 1.8 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.8 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.9 is infra-red (IR) spectrum of Homoharringtonine hydrogen itaconate in the solid state. FIG. 1.9 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.9 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.10 is infra-red (IR) spectrum of salt named homoharringtonine hydrogen fumarate in the solid state. FIG. 1.10 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.10 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.11 is infra-red (IR) spectrum of Homoharringtonine hydrogen tartronate in the solid state. FIG. 1.11 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.11 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.12 is infra-red (IR) spectrum of Homoharringtonine malonate in the solid state. FIG. 1.12 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.12 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.13 is infra-red (IR) spectrum of Homoharringtonine dihydrogen citrate in the solid state. FIG. 1.13 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.13 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 1.14 is infra-red (IR) spectrum of Homoharringtonine salicyclate in the solid state. FIG. 1.14 (i) is IR(ATR) spectrum in the crystalline state. FIG. 1.14 (ii) is IR(ATR) spectrum in the amorphous state (film).
• FIG. 2.2.1 is single crystal x-ray diffraction of homoharringtonine base, form A (ORTEP-3 software).
• FIG. 2.2.2 is single crystal x-ray diffraction of homoharringtonine base, form B (ORTEP-3 software).
• FIG. 2.2.3 is single crystal x-ray diffraction of homoharringtonine base, form B with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.3.1 is single crystal x-ray diffraction of homoharringtonine hydrogen (2S)-(−)-malate (ORTEP-3 software).
• FIG. 2.3.2 is single crystal x-ray diffraction of homoharringtonine hydrogen (2S)-(−)-malate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.3.3 is x-ray powder diffraction (XRPD) of homoharringtonine hydrogen (2S)-(−)-malate.
• FIG. 2.4.1 is single crystal X-ray diffraction of homoharringtonine hydrogen (2R)-(+)-malate (created by ORTEP-3 software).
• FIG. 2.4.2 is single crystal X-ray diffraction of homoharringtonine hydrogen (2R)-(+)-malate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.4.3 is X-ray powder diffraction (XRPD) of homoharringtonine hydrogen (2R)-(+)-malate.
• FIG. 2.5.1 is single crystal X-ray diffraction of homoharringtonine hydrogen (2S,3S)-(−)-tartarate (created by ORTEP-3 software).
• FIG. 2.5.2 is single crystal X-ray diffraction of homoharringtonine hydrogen (2S,3S)-(+)-tartarate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.5.3 is X-ray powder diffraction (XRPD) of homoharringtonine hydrogen (2S,3S)-(−)-tartarate.
• FIG. 2.6.1 is single crystal X-ray diffraction of homoharringtonine hydrogen (2R,3R)-(+)-tartarate (created by ORTEP-3 software).
• FIG. 2.6.2 is single crystal X-ray diffraction of homoharringtonine hydrogen (2R,3R)-(+)-tartarate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.6.3 is X-ray powder diffraction (XRPD) of homoharringtonine hydrogen (2R,3R)-(+)-tartarate.
• FIG. 2.7.1 is X-ray powder diffraction (XRPD) of homoharringtonine hydrogen (2′″S)-citramalate.
• FIG. 2.8.1 is single crystal X-ray diffraction of homoharringtonine hydrogen (2R)-(−)-citramalate (created by ORTEP-3 software).
• FIG. 2.8.2 is single crystal X-ray diffraction of homoharringtonine hydrogen (2R)-(−)-citramalate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.8.3 is X-ray powder diffraction (XRPD) of homoharringtonine hydrogen (2R)-(−)-citramalate.
• FIG. 2.9.1 is single crystal X-ray diffraction of homoharringtonine hydrogen itaconate (created by ORTEP-3 software).
• FIG. 2.9.2 is single crystal X-ray diffraction of homoharringtonine hydrogen itaconate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.10.1 is X-ray powder diffraction (XRPD) of homoharringtonine hydrogen fumarate.
• FIG. 2.11.1 is single crystal X-ray diffraction of homoharringtonine dihydrogen citrate (created by ORTEP-3 software).
• FIG. 2.11.2 is single crystal X-ray diffraction of homoharringtonine dihydrogen citrate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 2.11.3 is X-ray powder diffraction (XRPD) of homoharringtonine dihydrogen citrate.
• FIG. 2.12.1 is single crystal X-ray diffraction of homoharringtonine salicyclate (created by ORTEP-3 software).
• FIG. 2.12.2 is single crystal X-ray diffraction of homoharringtonine salicyclate (PLUTO drawing).
• FIG. 2.12.3 is single crystal X-ray diffraction of homoharringtonine salicyclate (stick drawing).
• FIG. 2.12.4 is single crystal X-ray diffraction of homoharringtonine salicydate with corresponding packing with unit cell content (PLUTO drawing, ORTEP-3 software).
• FIG. 3.1 is DSC pattern of homoharringtonine base.
• FIG. 3.2 is DSC pattern of homoharringtonine hydrogen (2S)-malate.
• FIG. 3.3 is DSC pattern of homoharringtonine hydrogen (2R)-malate.
• FIG. 3.4 is DSC pattern of homoharringtonine hydrogen (2S,3S)-tartrate.
• FIG. 3.5 is DSC pattern of homoharringtonine hydrogen (2R,3R)-tartrate.
• FIG. 3.6 is DSC pattern of homoharringtonine hydrogen (2S)-citramalate.
• FIG. 3.7 is DSC pattern of homoharringtonine hydrogen (2R)-citramalate.
• FIG. 3.8 is DSC pattern of homoharringtonine hydrogen succinate.
• FIG. 3.9 is DSC pattern of homoharringtonine hydrogen itaconate.
• FIG. 3.10 is DSC pattern of homoharringtonine hydrogen fumarate.
• FIG. 3.11 is DSC pattern of homoharringtonine hydrogen tartronate.
• FIG. 3.12 is DSC pattern of homoharringtonine hydrogen malonate.
• FIG. 3.13 is DSC pattern of homoharringtonine dihydrogen citrate.
• FIG. 3.14 is DSC pattern of homoharringtonine salicyclate.
DETAILED DESCRIPTION
• In one embodiment, the crystalline salts of the invention are used as drug substance for blending alone or in combination with other therapeutical agents in pharmaceutical composition useful as immunomodulating agents, particularly in using oral or parenteral modes of administration.
• A major embodiment of the invention is a new efficient process of purification of natural, semi-synthetic or synthetic version of harringtonines and their analogs using formation of a crystallogenic salt and its fractional crystallization in organic solvents, all the resulting purified compounds having the same level of purity.
• Another aspect of the invention is a new efficient process of purification of natural homoharringtonine using formation of crystallogenic salts and their fractional crystallization in organic solvents giving the same level of purity as homoharringtonine of hemi/semi-synthetic origin.
• Another aspect of the invention is a new efficient process of purification of natural harringtonine using formation of crystallogenic salts and their fractional crystallization in organic solvents giving the same level of purity as harringtonine of hemi/semi-synthetic origin.
• In one embodiment, the present invention relates to a harringtonines salt in the crystalline state exhibiting a protonated nitrogen seen in solid state analysis and having formula 1,
• 
• comprising solvate, made by reacting a cephalotaxine ester having formula 2,
• 
• in which R¹ is, but not limited to, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, and R² is, independently, but not limited to H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocydoalkyl, with an acid having general formula AH in a crystallization solvent, wherein the said salt has a water or alkohol solubility ranged approximately from 5 mg/mL to approximately 100 mg/Ml.
• In a preferred embodiment, the acid having general formula AH is an organic acid. In a preferred embodiment, the organic acid is selected among the following list: fumaric, maleic, citramalic, malic, tartaric, tartronic, succinic, itaconic, citric acid or salicylic acid.
• A preferred embodiment of the invention is a crystalline homohaningtonine hydrogen 2S-malate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.2, the same single crystal X-ray diffractogram as set out in FIGS. 2.3.1 and 2.3.2, the same X-ray powder pattern as set out in FIG. 2.3.3 and the same DSC curve as set out in FIG. 3.2.
• A further preferred embodiment of the invention provides a crystalline homoharringtonine hydrogen 2R-malate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.3, the same single crystal X-ray diffractogram as set out in FIGS. 2.4.1 and 2.4.2, the same X-ray powder pattern as set out in FIG. 2.4.3 and the same DSC curve as set out in FIG. 3.3.
• A further preferred aspect of the invention is a crystalline homoharringtonine hydrogen (2S,3S)-tartrate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.4, the same single crystal X-ray diffractogram as set out in FIGS. 2.5.1 and 2.5.2, the same X-ray powder pattern as set out in FIG. 2.5.3 and the same DSC curve as set out in FIG. 3.4.
• Yet, a further embodiment of the invention is a crystalline homoharringtonine hydrogen (2R,3R)-tartrate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.5, the same single crystal X-ray diffractogram as set out in FIGS. 2.6.1 and 2.6.2, the same X-ray powder pattern as set out in FIG. 2.6.3 and the same DSC curve as set out in FIG. 3.5.
• Yet, another embodiment of the invention provides a crystalline homoharringtonine hydrogen (2S)-citramalate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.6, the same X-ray powder pattern as set out in FIG. 2.7.1 and the same DSC curve as set out in FIG. 3.6.
• Yet, a preferred aspect of this invention is a crystalline homoharringtonine hydrogen (2R)-citramalate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.7, the same single crystal X-ray diffractogram as set out in FIGS. 2.8.1 and 2.8.2, the same X-ray powder pattern as set out in FIG. 2.8.3 and the same DSC curve as set out in FIG. 3.7.
• Yet, another preferred aspect of this invention provides a crystalline homoharringtonine hydrogen succinate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.8, and the same DSC curve as set out in FIG. 3.8.
• Yet, a further preferred aspect of this invention is a crystalline homoharringtonine hydrogen itaconate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.9, the same single crystal X-ray diffractogram as set out in FIGS. 2.9.1 and 2.9.2 and the same DSC curve as set out in FIG. 3.9.
• Yet, a preferred aspect of this invention provides a crystalline homoharringtonine hydrogen fumarate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.10, the same X-ray powder pattern as set out in FIG. 2.10.1 and the same DSC curve as set out in FIG. 3.10.
• Yet, an another aspect of the invention provides a crystalline homohamrngtonine hydrogen tartronate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.11 and the same DSC curve as set out in FIG. 3.11.
• In addition, another embodiment provides a crystalline homoharringtonine hydrogen malonate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.12 and the same DSC curve as set out in FIG. 3.12.
• Moreover, a preferred embodiment of this invention provides a crystalline homoharringtonine dihydrogen citrate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.13, the same single crystal X-ray diffractogram as set out in FIGS. 2.11.1 and 2.11.2, the same X-ray powder pattern as set out in FIG. 2.11.3 and the same DSC curve as set out in FIG. 3.13.
• Also, a preferred aspect of this invention provides a crystalline homoharringtonine hydrogen salicylate having substantially the same IR spectrum, in the solid state as set out in FIG. 1.14, the same single crystal X-ray diffractogram as set out in FIGS. 2.12.1, 2.12.2, 2.12.3 and 2.12.4 and the same DSC curve as set out in FIG. 3.14.
• Yet, a preferred aspect of this invention provides a pharmaceutical composition comprising an effective amount of one of the salts of this invention, together with one or more pharmaceutical acceptable inactive components such as carriers, excipients, adjuvants or diluents.
• Yet, a preferred aspect of this invention provides a pharmaceutical dosage form dedicated to an oral mode of administration selected among, for example, capsules, dragees, emulsions, granules, pills, powders, solutions, suspensions, tablets, microemulsions, elixirs, syrups, tea or powders for reconstitution.
• Yet, an another aspect of this invention provides a pharmaceutical dosage form dedicated to a subcutaneous mode of administration in non-acidic condition allowing a good locale tolerance.
• Another aspect of the invention is the use of at least the solid form of one salt described in the invention for preparing the above pharmaceutical composition as (i) chemotherapeutic agent, (ii) enhancer of other chemotherapeutic agents (iii) after failure of other agents (iv) for inhibiting tumors growth in animal, (v) for inhibiting mammalian parasites, (vi) as immunosuppressive agent, or (vii) as reversal agent.
• A preferred embodiment of the invention describes a method for treating mammalian tumors which comprises oral administering to a mammal an antitumor effective amount of the solid form of one salt described in this invention.
• A further preferred embodiment of the invention describes a method for treating mammalian tumors which comprises implantable pharmaceutical preparation administering to a mammal an antitumor effective amount of the solid form of at least one salt described in this invention.
• Yet, invention is also concerned with the use of solid form of the salts of the invention as defined above, for the preparation of pharmaceutical compositions for the treatment of cancer, particularly brain cancer such as for example, but not limited to, neuroblastoma and eventually their metastasis, lung cancer such as for example non-small cells lung carcinoma eventually their metastasis, ovarian high-grade carcinoma, breast cancer including triple negative breast carcinoma and eventually their metastasis, and pancreatic cancer including ductal adenocarcinoma, this therapy being given alone or combined with at least another chemotherapeutic agent, eventually combined with radiotherapy.
• Another embodiment of the present invention relates to a method of treating cancer, particularly brain cancer such as for example, but not limited to, neuroblastoma and eventually their metastasis, and lung cancer such as for example non-small cells lung carcinoma eventually their metastasis, ovarian high-grade carcinoma, breast cancer including triple negative breast carcinoma and eventually their metastasis, and pancreatic cancer including ductal adenocarcinoma, comprising administering to a patient or an animal in need thereof a pharmaceutical composition comprising solid form of the salts of the invention, said pharmaceutical composition being administered alone or combined with at least another chemotherapeutic agent, eventually combined with radiotherapy.
• Furthermore, invention also deals with the use of solid form of the salts of the invention as defined above, for the preparation of pharmaceutical compositions for the treatment of autoimmune diseases, such as for example but not limited to multiple sclerosis, psoriasis, rheumatoid arthritis, dermatomyositis, Hashimoto's thyroiditis, systemic lupus erythematosus, this therapy being given alone or combined with at least another chemotherapeutic agent, said at least another chemotherapeutic agent being eventually combined with radiotherapy, or with at least another immunomodulating agent. Another embodiment of the present invention relates to a method of treating autoimmune diseases, such as for example but not limited to multiple sclerosis, psoriasis, rheumatoid arthritis, dermatomyositis, Hashimoto's thyroiditis, systemic lupus erythematosus, comprising administering to a patient or an animal in need thereof a pharmaceutical composition comprising solid form of the salts of the invention, said pharmaceutical composition being administered alone or combined with at least another chemotherapeutic agent, said at least another chemotherapeutic agent being eventually combined with radiotherapy.
• Finally, the invention is also concerned with the use of solid form of the salts of the invention as defined above, for the preparation of pharmaceutical compositions for the treatment of leukemias particularly acute myelod leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelosclerosis, and/or lymphoma such as but not limited to a multiple myeloma, a Hodgkin disease or a Burkitt lymphoma, said therapy being given alone or combined with at least another chemotherapeutic agent and/or with radiotherapy.
• Another embodiment of the present invention relates to a method of treating leukemias particularly acute myelod leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelosclerosis, and/or, said method comprising administering to a patient or an animal in need thereof a pharmaceutical composition comprising solid form of the salts of the invention, said pharmaceutical composition being administered alone or combined with at least another chemotherapeutic agent, including the targeted one, eventually combined with radiotherapy.
• In a preferred embodiment, the patient in need thereof according to the present invention is a de novo patient or a patient for which other therapy as failed to treat the disease from which he suffers.
Example 1: General Procedure for Experimental Methods
• 1.1 General Procedures for Salts Preparation
• Cation and anion components are dissolved separately in a solvent at a concentration close of saturation and at a temperature close of boiling then both solutions are mixed under stirring then slowly cooled and evaporated. After a period ranging from a few minutes up to several days, crystal salt is collected. A sample of the batch of crystals is kept suspended in its mother liquors for the subsequent X-ray diffraction analysis. The remainder of the batch was dried under vacuum for further solid characterization, comparative stability studies and drug formulation.
• 1.2 General Procedures for Solid State Characterization
• Single Crystal X-Ray Diffractions Material and Methods
• KappaCCD, Nonius diffractometer, Mo—K_α radiation (λ=0.71073 Å). The structure was solved by direct methods using the SHELXS-97 program [Sheldrick G. M., Acta Cryst. A64 (2008), 112-122], and then refined with full-matrix least-square methods based on F² (SHELXL-2013) [Sheldrick G. M., (2013)] with the aid of the WINGX [L. J. Farrugia, J. Appl. Cryst., 2012, 45, 849-854] program. All non-hydrogen atoms were refined with anisotropic atomic displacement parameters. Except nitrogen and oxygen linked hydrogen atoms that were introduced in the structural model through Fourier difference maps analysis, H atoms were finally included in their calculated positions.
• Collected information: atomic positions; unit cell composition; crystal packing anisotropic displacement parameters; bond lengths, dihedral and torsion angles, hydrogen bounding.
• Original files with all parameters are includes on a CD and may be visualized and handled in using ORTEP-3 software (ORTEP=Oak Ridge Thermal-Ellipsoid Plot Program) available free of charge on the Internet:
• http://www.chem.gla.ac.uk/˜louis/software/ortep3/
• X-Ray Diffraction Powder
• Diagrams were measured on a Bruker AXS D8 Advance diffractometer, Bragg-Brentano geometry (θ-2 θ), CuK α=1.5406 Å, 600 ms/pixel, rotation: 0.25/sec. For each chart, the calculated pattern from the single crystal structure, when available, is upped mentioned.
• Differential Scanning Calorimetry (DSC)
• The DSC analysis was performed using a Perkin Elmer DSC 4000 apparatus. The scan rate was 5° C./min and the scanning range of of temperature 40 to 230° C. The accurately weighed quantity was ranged from 1 to 3 mg. All operations were performed under nitrogen atmosphere. The measured values were the Onset, the Peak and the value of the free enthalpy variation. The eventual product decomposition and the vaporization of solvent crystallization (methanol and/or water) were recorded. The value of the change in free energy, was given only as a guideline to assess the endothermicity or exotermicity of the transition.
• Melting Point Checking
• Melting points were measured manually for visual checking of the one determined with DSC. A Bücchi B-545 melting point apparatus was used and mp are uncorrected.
• Infrared Spectra
• All vibrational spectra were recorded on a Perkin Elmer IR FT Spectrum 2 apparatus equipped with diamond ATR accessory that is to say using Attenuated Total Reflection technique. The crystalline solids were crushed directly by in situ compression on the diamond window and the amorphous state has been demonstrated by dissolving the product in deuterated methanol then generating the film by in situ evaporation on the diamond window.
• 1.3 General Procedures for Liquid State and Solution Characterizations
• Nuclear Magnetic Resonance
• NMR spectra were recorded automatically on a Bruker Avance III spectrometer NanoBay—400 MHz (9.4 Tesla magnet) with a BBFO+probe and sampler 120 positions, allows for automatic mode NMR experiments one and two dimensions mainly for nuclei: 1H, 2H, 11B, 13C, 15N, 19F, 27Al, 31P, 119Sn or on Bruker Avance III—600 MHz spectrometer.
• Dissolving salts for ¹³C NMR: 30 mg of compound were dissolved in 600 μL (5% m/V) of methanol D₄ or deuterium oxyde (or both if specified)
• Water suppression: The irradiation technique known as ‘watergate’ (Selective pulse flanked by gradient pulses) was used for proton NMR in the presence of D₂O and/or MOD₄ as solvents.
• High Performance Liquid Chromatography
• Routine experiments were performed on a Waters HPLC-MS-DAD coupled system (3100 pump, DAD 996 detector, 3100 mass detector).
• Solubility Determination
• Solubility in water at 25° C. was measured semi-quantitatively at a threshold of 5 g per 100 mL. All the homoharringtonine salts described in the below examples, unless otherwise stated, are soluble at this threshold. Homoharringtonine base itself is soluble at a threshold mower than 0.1 g per mL
Example 2: Analyses of Homoharringtonine Base for Comparison with its Salts
• 
• 2.1 Analysis of Homoharringtonine Base Alkaloid
• Commercial homoharringtonine is provided by Sigma Aldrich.NMR spectra were performed in deuterated methanol for comparison with salt in the same solvent
• By methanol recrystallisation of a commercial alkaloid from natural source, it results fine white prisms (mp 145-146°, by DSC, see FIG. 3.1) used for all experiences.
• ¹H NMR (400 MHz, Benzene-d₆) δ 6.54 (s, 1H), 6.46 (s, 1H), 6.21-6.12 (m, 1H), 5.47 (d, J=1.4 Hz, 1H), 5.33 (d, J=1.4 Hz, 1H), 4.67 (s, 1H), 3.43 (d, J=9.8 Hz, 1H), 3.34 (s, 3H), 3.28 (s, 3H), 2.83 (td, J=8.5, 4.5 Hz, 1H), 2.75 (dd, J=11.5, 4.5 Hz, 1H), 2.55 (dd, J=10.8, 7.5 Hz, 1H), 2.41 (dd, J=16.2, 6.9 Hz, 2H), 2.23-2.11 (m, 2H), 1.78 (m, 1H), 1.67-1.56 (m, 2H), 1.48 (m, 5H), 1.34-1.19 (m, 2H), 1.04 (d, J=6.7 Hz, 6H).
• ¹H NMR (300 MHz, Chloroform-d) δ 6.62 (s, 1H), 6.54 (s, 1H), 6.00 (d, J=9.8 Hz, 1H), 5.87 (s, 2H), 5.05 (s, 1H), 3.78 (d, J=9.8 Hz, 1H), 3.68 (s, 3H), 3.57 (s, 3H), 3.52 (s, 1H), 3.20-3.04 (m, 2H), 3.01-2.88 (m, 1H), 2.60 (t, J=7.2 Hz, 1H), 2.38 (dd, J=13.7, 6.3 Hz, 1H), 2.26 (d, J=16.5 Hz, 1H), 2.10-1.97 (m, 1H), 1.91 (d, J=16.5 Hz, 1H), 1.75 (s, OH), 1.39 (dd, J=13.5, 6.4 Hz, 5H), 1.19 (s, 7H).
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.7 (s, 1H), 6.59 (s, 1H), 5.98 (dd, J=9.8, 0.8 Hz, 1H), 5.89 (d, J=1.2 Hz, 1H), 5.85 (d, J=1.2 Hz, 1H), 5.22 (d, J=0.8 Hz, 1H), 3.89 (d, J=9.8 Hz, 1H), 3.70 (s, 3H), 3.55 (s, 3H), 3.20 (ddd, J=14.1, 12.4, 7.9 Hz, 1H), 2.96 (m, 1H), 2.88 (m, 1H), 2.64 (dd, J=11.4, 7.6 Hz, 1H), 2.44 (dd, J=14.3, 6.8 Hz, 1H), 2.17 (d, J=16.1 Hz, 1H), 2.03 (m, 1H), 1.95 (m, 1H), 1.90 (d, J=16.1 Hz, 1H), 1.49-1.30 (m, 5H), 1.25 (dd, J=9.8, 5.8 Hz, 1H), 1.17 (s, 3H), 1.16 (s, 3H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR (101 MHz, MeOD) δ 174.68, 171.76, 159.97, 148.21, 147.32, 134.49, 129.88, 114.02, 110.86, 102.10, 100.74, 76.03, 75.52, 72.14, 71.35, 58.04, 56.48, 54.60, 52.00, 49.64, 44.89, 44.15, 43.86, 40.87, 32.08, 29.27, 29.01, 20.82, 19.19.
• IR (KBr, solid), cm⁻¹ 3551.9, 3412.3, 3000.4, 2976.1, 2966.0, 2958.6, 2911.4, 2876.0, 2814.4, 2740.8, 1743.0, 1653.5, 1624.7, 1505.3, 1488.1, 1454.8, 1436.1, 1411.2, 1392.8, 1377.7, 1367.2, 1346.3, 1306.4, 1274.3, 1261.5, 1230.0, 1190.8, 1162.1, 1135.3, 1119.9, 1082.0, 1027.9, 1000.5, 932.1, 900.6, 879.3, 854.2, 827.3, 804.9, 795.2, 772.4, 762.9, 738.3, 705.7, 674.0, 661.4, 610.8, 556.7, 540.9, 522.1, 512.8, 503.3. See FIG. 1.1
• A) Single Crystal X Ray Diffraction of Homoharringtonine Base (Form A).
• See Corresponding FIG. 2.2.1
• From a suspension in its mother liquor, a suitable single crystal of size 0.5×0.4×0.4 mm was finally selected and implemented on the diffractometer.

• Structural data:

  Formula weight	545.61
  Temperature	293(2)K

  Wavelength

  0.71073

  Å

  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions	a = 11.9512(2) Å, α = 90°
  	b = 15.2211(2) Å, β = 90°
  	c = 15.9670(2) Å, γ = 90°

  Volume

  2904.56(7)

  Å3

  Z, Calculated density

  4, 1.248 (g · cm−1)

  Absorption coefficient

  0.092

  mm−1

  F(000)	1168
  Crystal size	0.5 × 0.4 × 0.4 mm
  Crystal color	colourless
  Theta range for data collection	2.881 to 29.046°
  h_min, h_max	−16, 16
  k_min, k_max	−20, 20
  l_min, l_max	−21, 21
  Reflections collected/unique	35627/7642 [aR(int) = 0.049]
  Reflections [I > 2σ]	5925
  Completeness to theta_max	0.99
  Absorption correction type	none
  Refinement method	Full-matrix least-squares on F2
  Data/restraints/parameters	7642/0/352
  bGoodness-of-fit	1.034
  Final R indices [I > 2σ]	cR1 = 0.0495, dwR2 = 0.1256
  R indices (all data)	cR1 = 0.0719, dwR2 = 0.1411
  Largest diff. peak and hole	0.284 and −0.203 e.Å−3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
  Atom numbering of FIG. 2.2.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.9387(2)	0.25439(15)	0.89639(14)	1	0.0374(5)
  H1	1.0075	0.2226	0.8823	1	0.045
  C2	0.9724(2)	0.34995(16)	0.90497(14)	1	0.0390(5)
  C3	1.0805(2)	0.37308(17)	0.87926(17)	1	0.0442(5)
  H3	1.1276	0.3319	0.8546	1	0.053
  C4	1.1150(2)	0.45761(19)	0.89130(17)	1	0.0494(6)
  C5	1.2096(4)	0.5829(2)	0.8960(3)	1	0.0862(12)
  H5A	1.2163	0.6192	0.8463	1	0.103
  H5B	1.2695	0.5986	0.9342	1	0.103
  C6	1.0469(3)	0.51945(17)	0.92762(18)	1	0.0528(6)
  C7	0.9399(2)	0.49967(18)	0.95274(17)	1	0.0498(6)
  H7	0.8939	0.5421	0.9765	1	0.06
  C8	0.9026(2)	0.41337(17)	0.94127(15)	1	0.0434(5)
  C9	0.7884(2)	0.38828(18)	0.97226(17)	1	0.0493(6)
  H9A	0.7497	0.3553	0.9291	1	0.059
  H9B	0.7455	0.4411	0.9836	1	0.059
  C10	0.7951(3)	0.3328(2)	1.05191(18)	1	0.0569(7)
  H10A	0.8046	0.3714	1.0997	1	0.068
  H10B	0.7251	0.3014	1.0592	1	0.068
  C11	0.8990(3)	0.2199(3)	1.12687(17)	1	0.0648(8)
  H11A	0.8277	0.1965	1.1455	1	0.078
  H11B	0.9302	0.256	1.1711	1	0.078
  C12	0.9767(5)	0.1482(3)	1.1039(2)	1	0.1012(16)
  H12A	1.0519	0.162	1.1227	1	0.121
  H12B	0.9536	0.0937	1.1303	1	0.121
  C13	0.9745(3)	0.1391(2)	1.0129(2)	1	0.0677(9)
  H13A	0.949	0.0808	0.9975	1	0.081
  H13B	1.0488	0.148	0.99	1	0.081
  C14	0.8927(2)	0.20973(17)	0.97856(14)	1	0.0426(5)
  C15	0.7844(2)	0.16871(17)	0.95088(16)	1	0.0457(5)
  H15	0.7362	0.1387	0.9865	1	0.055
  C16	0.7655(2)	0.18031(16)	0.86960(15)	1	0.0407(5)
  C17	0.8541(2)	0.23162(15)	0.82622(14)	1	0.0374(5)
  H17	0.8905	0.1948	0.7839	1	0.045
  C18	0.8201(2)	0.31714(16)	0.70344(14)	1	0.0415(5)
  C19	0.7614(2)	0.39953(17)	0.67082(15)	1	0.0470(6)
  C20	0.7996(3)	0.48109(18)	0.71967(18)	1	0.0574(7)
  H20A	0.7501	0.5295	0.7059	1	0.069
  H20B	0.7916	0.4693	0.7791	1	0.069
  C21	0.9168(4)	0.5087(2)	0.7031(2)	1	0.0712(10)
  C22	1.1000(4)	0.4595(4)	0.6716(3)	1	0.1074(16)
  H22A	1.1041	0.4831	0.6159	1	0.161
  H22B	1.1425	0.4061	0.6745	1	0.161
  H22C	1.1301	0.5014	0.7106	1	0.161
  C23	0.6346(2)	0.38782(19)	0.67748(17)	1	0.0525(6)
  H23A	0.6135	0.3894	0.7361	1	0.063
  H23B	0.5983	0.4369	0.6499	1	0.063
  C24	0.5914(3)	0.3023(2)	0.6389(2)	1	0.0590(7)
  H24A	0.6233	0.2952	0.5834	1	0.071
  H24B	0.6159	0.2531	0.6729	1	0.071
  C25	0.4642(3)	0.3012(2)	0.6326(2)	1	0.0665(8)
  H25A	0.4338	0.3092	0.6884	1	0.08
  H25B	0.4411	0.3513	0.5994	1	0.08
  C26	0.4115(3)	0.2193(3)	0.5950(2)	1	0.0754(10)
  C27	0.2855(4)	0.2319(4)	0.5904(4)	1	0.1200(19)
  H27A	0.2691	0.2858	0.5617	1	0.18
  H27B	0.2553	0.2343	0.6461	1	0.18

• Single Crystal X Ray Diffraction of Homoharringtonine Base (Form B)
• See Corresponding FIGS. 2.2.2 and 2.2.3
• From a suspension in its mother liquor, a suitable single crystal of size 0.43×0.29×0.18 mm was finally selected and implemented on the diffractometer.

• Structural data
  Empirical formula	C31H49N O12
  Extended formula	C29H39N O9, 2(CH4O), H2O
  Formula weight	627.71
  Temperature	150(2)K

  Wavelength

  0.71073

  Å

  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions	a = 11.7738(10) Å, α = 90°
  	b = 14.3907(13) Å, β = 90°
  	c = 19.1368(15) Å, γ = 90°

  Volume

  3242.4(5)

  Å3

  Z, Calculated density

  4, 1.286 (g · cm−1)

  Absorption coefficient

  0.098

  mm−1

  F(000)	1352
  Crystal size	0.43 × 0.29 × 0.18 mm
  Crystal color	colourless
  Theta range for data collection	3.02 to 27.46°
  h_min, h_max	−15, 13
  k_min, k_max	−18, 18
  l_min, l_max	−24, 19
  Reflections collected/unique	16236/4103 [aR(int) = 0.0334]
  Reflections [I > 2σ]	3764
  Completeness to theta_max	0.99
  Absorption correction type	multi-scan
  Max. and min. transmission	0.982, 0.874
  Refinement method	Full-matrix least-squares on F2
  Data/restraints/parameters	4103/2/421
  bGoodness-of-fit	1.031
  Final R indices [I > 2σ]	cR1 = 0.0346, dwR2 = 0.0871
  R indices (all data)	cR1 = 0.039, dwR2 = 0.09
  Largest diff. peak and hole	0.259 and −0.2 e.Å−3

• Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
• U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIGS. 2.2.2 and 2.2.3 corresponds to below table.

• Atom	x	Y	z	occ.	U(eq)
  C1	0.14461(16)	0.92123(13)	0.19855(10)	1	0.0185(4)
  H1	0.1645	0.9474	0.2424	1	0.022
  C2	0.13507(16)	0.96935(13)	0.14015(10)	1	0.0182(4)
  C3	0.10057(15)	0.91236(13)	0.07788(10)	1	0.0162(4)
  H3	0.0245	0.9326	0.0604	1	0.019
  C4	0.09461(15)	0.81122(13)	0.10658(10)	1	0.0156(4)
  H4	0.0135	0.7915	0.1024	1	0.019
  C5	0.11993(15)	0.81891(13)	0.18697(10)	1	0.0173(4)
  C6	0.01795(18)	0.78404(16)	0.22996(10)	1	0.0236(4)
  H6A	−0.0435	0.831	0.2309	1	0.028
  H6B	−0.0124	0.7254	0.2103	1	0.028
  C7	0.06647(19)	0.76830(18)	0.30351(12)	1	0.0324(5)
  H7A	0.0543	0.8236	0.3334	1	0.039
  H7B	0.0307	0.7137	0.326	1	0.039
  C8	0.19354(19)	0.75150(15)	0.29115(10)	1	0.0250(4)
  H8A	0.2394	0.8	0.3146	1	0.03
  H8B	0.2164	0.69	0.3095	1	0.03
  N9	0.21006(14)	0.75555(11)	0.21387(8)	1	0.0190(3)
  C10	0.32858(17)	0.78051(14)	0.19706(11)	1	0.0214(4)
  H10A	0.3792	0.729	0.2115	1	0.026
  H10B	0.3502	0.8363	0.2243	1	0.026
  C11	0.34668(16)	0.80017(13)	0.11940(10)	1	0.0185(4)
  H11A	0.3221	0.8645	0.1092	1	0.022
  H11B	0.4288	0.7958	0.1088	1	0.022
  C12	0.28274(15)	0.73420(12)	0.07195(10)	1	0.0166(4)
  C13	0.16369(16)	0.74035(12)	0.06606(9)	1	0.0158(4)
  C14	0.10458(16)	0.68001(13)	0.02102(10)	1	0.0185(4)
  H14	0.0244	0.6838	0.0162	1	0.022
  C15	0.16632(17)	0.61550(13)	−0.01569(11)	1	0.0214(4)
  C16	0.28285(17)	0.60909(13)	−0.00929(11)	1	0.0215(4)
  C17	0.34324(16)	0.66697(13)	0.03421(10)	1	0.0196(4)
  H17	0.4234	0.6616	0.0385	1	0.023
  C18	0.2238(2)	0.49213(19)	−0.07619(17)	1	0.0473(7)
  H18A	0.2304	0.4778	−0.1266	1	0.057
  H18B	0.2144	0.433	−0.0504	1	0.057
  C19	0.19032(19)	1.11428(14)	0.18498(12)	1	0.0283(5)
  H19A	0.2613	1.0871	0.2022	1	0.042
  H19B	0.1334	1.1137	0.2224	1	0.042
  H19C	0.2041	1.1785	0.1701	1	0.042
  C21	0.15776(16)	0.96435(12)	−0.03634(9)	1	0.0155(3)
  C22	0.25991(16)	0.96278(12)	−0.08591(10)	1	0.0169(4)
  C23	0.29059(16)	0.86127(13)	−0.10429(10)	1	0.0188(4)
  H23A	0.3594	0.8612	−0.134	1	0.023
  H23B	0.3091	0.8276	−0.0607	1	0.023
  C24	0.19701(16)	0.80987(13)	−0.14192(10)	1	0.0187(4)
  C25	0.1561(2)	0.68927(17)	−0.22153(14)	1	0.0361(5)
  H25A	0.1117	0.7289	−0.2529	1	0.054
  H25B	0.1053	0.6598	−0.1875	1	0.054
  H25C	0.195	0.6412	−0.2488	1	0.054
  C31	0.36248(16)	1.00778(13)	−0.04883(10)	1	0.0195(4)
  H31A	0.3848	0.9679	−0.009	1	0.023
  H31B	0.4272	1.0094	−0.0819	1	0.023
  C32	0.34172(18)	1.10662(12)	−0.02159(11)	1	0.0212(4)
  H32A	0.3272	1.149	−0.0613	1	0.025
  H32B	0.2742	1.1072	0.0092	1	0.025
  C33	0.44570(19)	1.13955(14)	0.01904(12)	1	0.0273(5)
  H33A	0.5137	1.1282	−0.0102	1	0.033
  H33B	0.453	1.1004	0.0613	1	0.033
  C34	0.44740(19)	1.24164(14)	0.04199(11)	1	0.0248(4)
  C35	0.5515(2)	1.25841(17)	0.08801(15)	1	0.0416(6)
  H35A	0.5496	1.2159	0.128	1	0.062
  H35B	0.5509	1.3227	0.1048	1	0.062
  H35C	0.6206	1.2474	0.0607	1	0.062
  C36	0.4479(2)	1.30687(14)	−0.01973(12)	1	0.0311(5)
  H36A	0.4469	1.3713	−0.0031	1	0.047
  H36B	0.3805	1.2954	−0.0486	1	0.047
  H36C	0.5164	1.2963	−0.0477	1	0.047
  O1	0.14964(13)	1.06111(9)	0.12688(7)	1	0.0244(3)
  O2	0.12829(13)	0.55129(11)	−0.06415(9)	1	0.0329(4)
  O3	0.32361(13)	0.53951(11)	−0.05252(9)	1	0.0328(4)
  O4	0.18522(11)	0.92032(9)	0.02297(7)	1	0.0169(3)
  O5	0.06782(11)	1.00004(10)	−0.04854(7)	1	0.0215(3)
  O6	0.23721(13)	1.01397(10)	−0.14731(7)	1	0.0221(3)
  HO6	0.170(3)	1.007(2)	−0.1577(16)	1	0.0
  O7	0.09736(13)	0.82269(11)	−0.13360(9)	1	0.0326(4)
  O8	0.23961(13)	0.74537(10)	−0.18490(8)	1	0.0289(3)
  O9	0.34591(17)	1.25612(12)	0.08302(10)	1	0.0403(4)
  HO9	0.346(3)	1.315(2)	0.0956(15)	1	0.0
  C51	0.1062(3)	0.5267(2)	0.2091(2)	1	0.0688(11
  H51A	0.105	0.4613	0.1948	1	0.103
  H51B	0.0453	0.5604	0.1851	1	0.103
  H51C	0.0948	0.531	0.2597	1	0.103
  O52	0.21050(17)	0.56578(12)	0.19155(11)	1	0.0451(5)
  H52	0.204(3)	0.632(3)	0.1905(18)	1	0.068
  O61	0.03166(17)	1.03110(13)	−0.21801(10)	1	0.0431(4)
  H61	−0.026(3)	1.028(3)	−0.1858(18)	1	0.065
  C62	−0.0021(2)	0.96665(19)	−0.26999(14)	1	0.0428(6)
  H62A	0.0298	0.9852	−0.3152	1	0.064
  H62B	−0.0852	0.9655	−0.2731	1	0.064
  H62C	0.0257	0.9046	−0.2576	1	0.064
  O71	0.35707(17)	1.45528(12)	0.12174(10)	1	0.0408(4)
  H71A	0.410(2)	1.489(2)	0.0914(15)	1	0.061
  H71B	0.301(2)	1.498(2)	0.1443(16)	1	0.061

Example 3: Preparation and Analyses of Homoharringtonine Hydrogen (2S)-Malate (Synonymous: Homoharringtonine (2S)-Bimalate)
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial (2S)-(−)-malic acid (natural form) according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 205.4-207.7° C. from MeOH (measured by DSC, see FIG. 3.2). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• ¹H NMR (400 MHz. Methanol-d₄)* δ 6.79 (s, 1H), 6.74 (s, 1H), 6.09 (dd, J=9.6, 0.6 Hz, 1H), 5.96 (d, J=1.1 Hz, 1H), 5.93 (d, J=1.1 Hz, 1H), 5.33 (d, J=0.6 Hz, 1H), 4.24 (dd, J=7.4, 5.4 Hz, 1H), 4.16 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 3.54 (s, 3H), 3.50 (dd, J=9.5, 4.3 Hz, 1H), 3.42-3.32 (m, 1H), 3.21-3.10 (m, 1H), 2.76 (dd, J=15.9, 5.5 Hz, 1H), 2.71-2.62 (m, 1H), 2.48 (dd, J=15.8, 7.4 Hz, 1H), 2.26-2.05 (m, 4H), 1.94 (d, J=16.1 Hz, 2H), 1.47-1.29 (m, 5H), 1.29-1.17 (m, 1H), 1.15 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹H NMR (600 MHz, Deuterium oxide)* δ 6.84 (s, 1H), 6.76 (s, 1H), 6.01 (dd, J=9.6, 0.7 Hz, 1H), 5.95 (d, J=1.0 Hz, 1H), 5.94 (d, J=1.0 Hz, 1H), 5.34 (d, J=0.6 Hz, 1H), 4.31 (dd, J=8.2, 4.2 Hz, 1H), 4.19 (d, J=9.6 Hz, 1H), 3.76 (s, 3H), 3.52 (s, 3H), 3.52 (m, 1H), 3.42-3.32 (m, 1H), 3.30-3.23 (m, 1H), 3.22-3.15 (m, 1H), 2.76 (dd, J=16.0, 4.2 Hz, 1H), 2.74-2.68 (m, 1H), 2.57 (dd, J=16.0, 8.2 Hz, 1H), 2.36 (d, J=17.0 Hz, 1H), 2.29-2.08 (m, 2H), 1.99 s(d, J=16.9 Hz, 1H), 1.97-1.89 (m, 1H), 1.45-1.37 (m, 2H), 1.36-1.26 (m, 3H), 1.12 (s, 6H), 1.12-1.02 (m, 1H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR APT* (101 MHz, MeOD) δ 179.23, 176.13, 174.23, 171.61, 165.05, 149.76, 148.75, 130.92, 126.86, 114.85, 111.80, 102.86, 96.12, 78.09, 76.08, 74.35, 71.27, 69.35, 59.01, 54.21, 53.27, 52.07, 48.94, 44.76, 44.06, 41.80, 40.88, 40.52, 29.25, 29.23, 29.17, 19.95, 19.09.
• ¹³C NMR APT* (101 MHz, D₂O) δ 178.97, 176.21, 174.23, 171.93, 162.88, 147.83, 146.74, 129.74, 125.22, 113.38, 111.12, 101.62, 95.52, 76.98, 75.25, 73.68, 71.34, 68.50, 58.41, 52.95, 52.24, 51.25, 47.58, 42.71, 42.54, 40.00, 39.18, 38.76, 27.69, 27.58, 27.47, 18.58, 17.68. *APT=Attached Proton Test
• IR (Diamond ATR, solid) cm−1 3404, 2969, 2601, 1981, 1758, 1736, 1712, 1657, 1525, 1505, 1490, 1468, 1435, 1374, 1353, 1265, 1226, 1188, 1148, 1080, 1032, 983, 943, 925, 862, 830, 796, 770, 756, 708, 691, 674, 650, 615, 589, 565, 541, 510, 477. See FIG. 1.2
• IR (Diamond ATR, film) cm ⁻¹ 3422, 2964, 1742, 1656, 1596, 1506, 1490, 1440, 1373, 1266, 1224, 1168, 1084, 1033, 929, 710, 615, 566, 509, 477, 0, 983, 943, 925, 862, 830, 796, 770, 756, 708, 691, 674, 650, 615, 589, 565, 541, 510. See FIG. 1.2
• Solubility in neutral water higher than 60 mg/mL
• A. Single Crystal X-Ray Diffraction (See FIGS. 2.3.1 and 2.3.2)
• From a suspension in its mother liquor, a suitable single crystal of size 0.58×0.46×0.29 mm was finally selected and implemented on the diffractometer.

• Structural data
  Empirical formula	C33H45N O14
  Extended formula	C29H40N O9, C4H5O5
  Formula weight	679.7
  Temperature	150(2)K

  Wavelength

  0.71073

  Å

  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions	a = 11.488(2) Å, α = 90°
  	b = 15.399(3) Å, β = 90°
  	c = 18.825(4) Å, γ = 90°

  Volume

  3330.2(11)

  Å3

  Z, Calculated density

  4, 1.356 (g · cm−1)

  Absorption coefficient

  0.106

  mm−1

  F(000)	1448
  Crystal size	0.58 × 0.46 × 0.29 mm
  Crystal color	white
  Theta range for data collection	3.09 to 27.48°
  h_min, h_max	−14, 14
  k_min, k_max	−19, 13
  l_min, l_max	−18, 24
  Reflections collected/unique	28567/4233 [aR(int) = 0.1176]
  Reflections [I > 2σ]	2414
  Completeness to theta_max	0.998
  Absorption correction type	multi-scan
  Max. and min. transmission	0.970, 0.688
  Refinement method:	Full-matrix least-squares on F2
  Data/restraints/parameters	4233/0/440
  bGoodness-of-fit	1.038
  Final R indices [I > 2σ]:	cR1 = 0.0735, dwR2 = 0.1727
  R indices (all data):	cR1 = 0.1366, dwR2 = 0.2124
  Largest diff. peak and hole	0.555 and −0.27 e.Å−3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIG. 2.3.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.8902(5)	0.0603(4)	0.7067(3)	1	0.0450(15)
  H1	0.8742	0.0363	0.7521	1	0.054
  C2	0.8846(5)	0.0175(4)	0.6464(3)	1	0.0405(13)
  C3	0.9163(5)	0.0678(4)	0.5821(3)	1	0.0412(14)
  H3	0.9896	0.0445	0.5606	1	0.049
  C4	0.9359(4)	0.1614(4)	0.6109(3)	1	0.0355(13)
  H4	1.0189	0.1762	0.6007	1	0.043
  C5	0.9255(5)	0.1528(4)	0.6934(3)	1	0.0391(13)
  C6	1.0363(5)	0.1790(5)	0.7327(3)	1	0.0501(16)
  H6A	1.0975	0.1343	0.7269	1	0.06
  H6B	1.0662	0.2352	0.7148	1	0.06
  C7	0.9996(6)	0.1865(5)	0.8099(3)	1	0.0584(18)
  H7A	1.0501	0.2277	0.836	1	0.07
  H7B	1.0023	0.1293	0.8339	1	0.07
  C8	0.8744(6)	0.2204(5)	0.8049(3)	1	0.0539(17)
  H8A	0.8215	0.1843	0.834	1	0.065
  H8B	0.8701	0.2812	0.8219	1	0.065
  N9	0.8411(4)	0.2153(4)	0.7276(3)	1	0.0432(12)
  H9	0.8561	0.2696	0.7081	1	0.052
  C10	0.7137(5)	0.1984(5)	0.7172(3)	1	0.0496(16)
  H10A	0.6691	0.2495	0.7338	1	0.06
  H10B	0.6904	0.148	0.7467	1	0.06
  C11	0.6826(4)	0.1802(4)	0.6402(3)	1	0.0436(14)
  H11A	0.7034	0.1193	0.6287	1	0.052
  H11B	0.5974	0.1864	0.6341	1	0.052
  C12	0.7435(4)	0.2399(4)	0.5885(3)	1	0.0401(14)
  C13	0.8622(4)	0.2320(4)	0.5758(3)	1	0.0349(13)
  C14	0.9172(4)	0.2871(4)	0.5278(3)	1	0.0364(13)
  H14	0.9984	0.2823	0.5191	1	0.044
  C15	0.8516(5)	0.3487(4)	0.4933(3)	1	0.0441(15)
  C16	0.7360(5)	0.3568(4)	0.5058(4)	1	0.0464(15)
  C17	0.6788(5)	0.3043(4)	0.5538(3)	1	0.0437(15)
  H17	0.598	0.3115	0.563	1	0.052
  C18	0.7884(6)	0.4626(5)	0.4322(5)	1	0.076(2)
  H18A	0.8017	0.5203	0.4539	1	0.091
  H18B	0.7749	0.4707	0.3807	1	0.091
  C19	0.8154(7)	−0.1118(5)	0.6969(4)	1	0.066(2)
  H19A	0.8787	−0.115	0.7317	1	0.099
  H19B	0.7907	−0.1707	0.6841	1	0.099
  H19C	0.7496	−0.0802	0.7175	1	0.099
  C21	0.8355(4)	0.0154(4)	0.4745(3)	1	0.0382(13)
  C22	0.7306(5)	0.0234(4)	0.4248(3)	1	0.0412(14)
  C23	0.7103(5)	0.1202(4)	0.4059(3)	1	0.0379(13)
  H23A	0.6413	0.1246	0.3746	1	0.046
  H23B	0.6932	0.1527	0.4501	1	0.046
  C24	0.8129(5)	0.1618(4)	0.3693(3)	1	0.0409(14)
  C25	0.8695(6)	0.2717(5)	0.2887(4)	1	0.069(2)
  H25A	0.9088	0.31	0.3226	1	0.104
  H25B	0.8353	0.3065	0.2505	1	0.104
  H25C	0.9259	0.2308	0.2686	1	0.104
  C31	0.6209(5)	−0.0103(4)	0.4625(3)	1	0.0450(14)
  H31A	0.6041	0.028	0.5035	1	0.054
  H31B	0.5544	−0.006	0.4293	1	0.054
  C32	0.6293(5)	−0.1031(4)	0.4889(4)	1	0.0491(16)
  H32A	0.6941	−0.108	0.5233	1	0.059
  H32B	0.6462	−0.1422	0.4484	1	0.059
  C33	0.5166(6)	−0.1309(5)	0.5242(4)	1	0.0596(19)
  H33A	0.4518	−0.1174	0.4914	1	0.072
  H33B	0.5056	−0.0947	0.5672	1	0.072
  C34	0.5053(7)	−0.2260(5)	0.5462(4)	1	0.069(2)
  C35	0.6051(10)	−0.2507(6)	0.5911(5)	1	0.100(3)
  H35A	0.5942	−0.3101	0.6086	1	0.15
  H35B	0.6107	−0.2108	0.6315	1	0.15
  H35C	0.6769	−0.2477	0.563	1	0.15
  C36	0.3912(10)	−0.2401(7)	0.5849(6)	1	0.112(4)
  H36A	0.3267	−0.2205	0.5549	1	0.168
  H36B	0.3914	−0.2069	0.6293	1	0.168
  H36C	0.3818	−0.302	0.5955	1	0.168
  O31	0.5016(6)	−0.2752(4)	0.4798(3)	1	0.104(2)
  H31	0.4952	−0.3283	0.4889	1	0.156
  O1	0.8553(4)	−0.0674(3)	0.6348(2)	1	0.0543(11)
  O2	0.6901(4)	0.4222(3)	0.4640(3)	1	0.0625(13)
  O3	0.8872(4)	0.4087(3)	0.4432(2)	1	0.0560(13)
  O21	0.8226(3)	0.0660(2)	0.53083(19)	1	0.0371(9)
  O22	0.9152(3)	−0.0342(3)	0.4646(2)	1	0.0507(11)
  O23	0.7478(3)	−0.0256(3)	0.3627(2)	1	0.0426(10)
  H23	0.8145	−0.0155	0.3464	1	0.064
  O24	0.9138(3)	0.1434(3)	0.3794(2)	1	0.0522(12)
  O25	0.7785(4)	0.2240(3)	0.3248(3)	1	0.0561(12)
  C51	0.8039(5)	0.4264(5)	0.7157(4)	1	0.0518(17)
  C52	0.7548(6)	0.5067(5)	0.6770(4)	1	0.0531(17)
  H52	0.7672	0.5593	0.7073	1	0.064
  C53	0.6259(6)	0.4973(5)	0.6614(4)	1	0.060(2)
  H53A	0.606	0.5382	0.6226	1	0.072
  H53B	0.6125	0.4379	0.6431	1	0.072
  C54	0.5421(6)	0.5127(5)	0.7216(4)	1	0.065(2)
  O51	0.8885(4)	0.3887(3)	0.6897(3)	1	0.0557(12)
  O52	0.7540(6)	0.4053(4)	0.7716(3)	1	0.095(2)
  O53	0.8147(6)	0.5173(5)	0.6130(4)	1	0.100(2)
  H53	0.8805	0.4937	0.6161	1	0.15
  O54	0.5697(6)	0.4866(5)	0.7821(3)	1	0.097(2)
  H54	0.5978	0.4363	0.7791	1	0.146
  O55	0.4515(5)	0.5523(5)	0.7122(3)	1	0.110(3)

• B. X-Ray Powder Diffraction
• The sample is pure and there is a very good match between the experimental pattern and the calculated pattern (for view of diagrams and experimental details, see FIG. 2.3.3)
Example 4: Preparation and Analyses of Homoharringtonine Hydrogen (2R)-Malate (Diastereomer of Example 3)
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial (2R)-(+)-malic acid (unnatural form) according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 205-208° C. from MeOH (measured by DSC, see FIG. 3.3). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.3)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.80 (s, 1H), 6.74 (s, 1H), 6.09 (d, J=9.6 Hz, 1H), 5.97 (d, J=1.0 Hz, 1H), 5.93 (d, J=0.9 Hz, 1H), 5.33 (s, 1H), 4.26 (dd, J=7.4, 5.5 Hz, 1H), 4.17 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 3.55 (s, 3H), 3.53 (s, 1H), 3.34 (s, 2H), 3.22-3.12 (m, 1H), 2.77 (dd, J=15.9, 5.4 Hz, 1H), 2.72-2.64 (m, 1H), 2.49 (dd, J=15.9, 7.4 Hz, 1H), 2.29-2.05 (m, 4H), 1.95 (d, J=16.1 Hz, 2H), 1.48-1.18 (m, 6H), 1.16 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR APT* (101 MHz, Methanol-d₄) δ 179.21, 176.06, 174.25, 171.63, 165.07, 149.78, 148.77, 130.94, 126.88, 114.85, 111.80, 102.88, 96.10, 78.07, 76.09, 74.36, 71.28, 69.33, 59.00, 54.22, 53.31, 52.07, 44.77, 44.06, 41.76, 40.88, 40.54, 29.27, 29.22, 19.94, 19.10. *APT=Attached Proton Test
• IR (Diamond ATR, solid) cm ⁻¹ 3467, 3384, 2970, 2051, 1762, 1737, 1708, 1655, 1607, 1533, 1509, 1494, 1469, 1440, 1376, 1349, 1333, 1292, 1258, 1230, 1208, 1167, 1147, 1121, 1080, 1032, 985, 942, 926, 888, 865, 820, 771, 754, 717, 690, 675, 648, 616, 563, 542, 513, 476. See FIG. 1.3
• IR (Diamond ATR, film) cm ⁻¹ 3422, 2964, 1742, 1656, 1598, 1506, 1490, 1440, 1373, 1266, 1224, 1169, 1084, 1033, 929, 709, 567, 511. See FIG. 1.3
• A. Single Crystal X-Ray Diffraction (See FIGS. 2.4.1 and 2.4.2)
• From a suspension in its mother liquor, a suitable single crystal of size 0.55×0.48×0.4 mm was finally selected and implemented on the diffractometer.

• Structural data
  Empirical formula	C34H49N O15
  Extended formula	C29H40N O9, C4H5O5, CH4O
  Formula weight	711.74
  Temperature	150(2)K

  Wavelength

  0.71073

  Å

  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions:	a = 11.3958(8) Å, α = 90°
  	b = 15.5163(16) Å, β = 90°
  	c = 19.3680(16) Å, γ = 90°

  Volume

  3424.7(5)

  Å3

  Z, Calculated density

  4, 1.38 (g · cm−1)

  Absorption coefficient

  0.108

  mm−1

  F(000)	1520
  Crystal size	0.55 × 0.48 × 0.4 mm
  Crystal color	colourless
  Theta range for data collection	3.06 to 27.47°
  h_min, h_max	−14, 14
  k_min, k_max	−20, 11
  l_min, l_max	−25, 14
  Reflections collected/unique	14680/4317 [aR(int) = 0.0515]
  Reflections [I > 2σ]	3608
  Completeness to theta_max	0.989
  Absorption correction	type multi-scan
  Max. and min. transmission	0.958, 0.839
  Refinement method:	Full-matrix least-squares on F2
  Data/restraints/parameters	4317/0/474
  bGoodness-of-fit	1.034
  Final R indices [I > 2σ]:	cR1 = 0.0397, dwR2 = 0.0825
  R indices (all data):	cR1 = 0.0531, dwR2 = 0.0878
  Largest diff. peak and hole	0.26 and −0.238 e.Å−3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIG. 2.4.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.8742(2)	0.06078(16)	0.19603(12)	1	0.0184(5)
  H1	0.8565	0.0356	0.2395	1	0.022
  C2	0.8762(2)	0.01795(16)	0.13644(13)	1	0.0188(5)
  C3	0.9050(2)	0.07250(16)	0.07486(11)	1	0.0170(5)
  H3	0.9806	0.0529	0.0538	1	0.02
  C4	0.9198(2)	0.16514(15)	0.10526(11)	1	0.0162(5)
  H4	1.0039	0.1809	0.098	1	0.019
  C5	0.9039(2)	0.15418(16)	0.18536(12)	1	0.0174(5)
  C6	1.0098(2)	0.18290(17)	0.22700(12)	1	0.0235(6)
  H6A	1.037	0.2405	0.2119	1	0.028
  H6B	1.0752	0.1413	0.2222	1	0.028
  C7	0.9654(3)	0.18574(18)	0.30140(13)	1	0.0267(6)
  H7A	1.0095	0.2288	0.3288	1	0.032
  H7B	0.9732	0.1286	0.3237	1	0.032
  C8	0.8361(3)	0.21154(17)	0.29473(12)	1	0.0238(6)
  H8A	0.7851	0.1693	0.3186	1	0.029
  H8B	0.8226	0.2692	0.3151	1	0.029
  N9	0.81061(19)	0.21246(14)	0.21739(10)	1	0.0176(4)
  H9	0.825(3)	0.269(2)	0.2017(17)	1	0.05
  C10	0.6851(2)	0.19196(17)	0.20232(13)	1	0.0218(6)
  H10A	0.635	0.2391	0.2201	1	0.026
  H10B	0.6631	0.1385	0.227	1	0.026
  C11	0.6617(2)	0.18021(15)	0.12509(12)	1	0.0191(5)
  H11A	0.6845	0.121	0.1116	1	0.023
  H11B	0.5764	0.1864	0.1166	1	0.023
  C12	0.7267(2)	0.24357(15)	0.07984(12)	1	0.0173(5)
  C13	0.8483(2)	0.23587(15)	0.07084(11)	1	0.0158(5)
  C14	0.9095(2)	0.29500(15)	0.02929(12)	1	0.0183(5)
  H14	0.9918	0.2903	0.0226	1	0.022
  C15	0.8457(2)	0.35990(16)	−0.00131(12)	1	0.0200(5)
  C16	0.7266(2)	0.36742(16)	0.00808(13)	1	0.0208(5)
  C17	0.6642(2)	0.31099(15)	0.04811(12)	1	0.0188(5)
  H17	0.582	0.3171	0.0542	1	0.023
  C18	0.7889(2)	0.4844(2)	−0.04641(17)	1	0.0369(7)
  H18A	0.802	0.5311	−0.0125	1	0.044
  H18B	0.7814	0.5104	−0.0929	1	0.044
  C19	0.8404(3)	−0.11951(17)	0.18391(15)	1	0.0307(6)
  H19A	0.912	−0.1207	0.2119	1	0.046
  H19B	0.8203	−0.1782	0.1695	1	0.046
  H19C	0.7759	−0.0954	0.2113	1	0.046
  C21	0.8370(2)	0.02556(14)	−0.03526(12)	1	0.0158(5)
  C22	0.7342(2)	0.02954(15)	−0.08511(12)	1	0.0162(5)
  C23	0.7016(2)	0.12332(15)	−0.10139(12)	1	0.0187(5)
  H23A	0.6336	0.1238	−0.1332	1	0.022
  H23B	0.6773	0.1523	−0.0582	1	0.022
  C24	0.8000(2)	0.17318(15)	−0.13336(12)	1	0.0184(5)
  C25	0.8506(3)	0.2801(2)	−0.21480(17)	1	0.0398(8)
  H25A	0.8814	0.321	−0.1808	1	0.06
  H25B	0.8156	0.3119	−0.2534	1	0.06
  H25C	0.9146	0.2438	−0.232	1	0.06
  C31	0.6261(2)	−0.01467(15)	−0.05365(12)	1	0.0180(5)
  H31A	0.599	0.02	−0.0139	1	0.022
  H31B	0.5625	−0.0146	−0.0885	1	0.022
  C32	0.6456(2)	−0.10722(15)	−0.02934(12)	1	0.0181(5)
  H32A	0.7012	−0.1076	0.0099	1	0.022
  H32B	0.6803	−0.1416	−0.0673	1	0.022
  C33	0.5293(2)	−0.14767(15)	−0.00701(13)	1	0.0196(5)
  H33A	0.4777	−0.151	−0.048	1	0.024
  H33B	0.4913	−0.1082	0.0264	1	0.024
  C34	0.5349(2)	−0.23726(16)	0.02570(12)	1	0.0202(5)
  C35	0.4125(2)	−0.26450(18)	0.04804(15)	1	0.0280(6)
  H35A	0.4172	−0.3188	0.0737	1	0.042
  H35B	0.363	−0.2724	0.0072	1	0.042
  H35C	0.3785	−0.2198	0.0777	1	0.042
  C36	0.5878(3)	−0.30546(16)	−0.02198(14)	1	0.0261(6)
  H36A	0.6674	−0.2881	−0.0353	1	0.039
  H36B	0.5391	−0.3111	−0.0634	1	0.039
  H36C	0.591	−0.3609	0.0022	1	0.039
  O1	0.85935(16)	−0.06660(11)	0.12358(9)	1	0.0246(4)
  O2	0.88492(17)	0.42476(12)	−0.04504(10)	1	0.0291(5)
  HO2	0.832(3)	−0.035(2)	−0.1469(17)	1	0.05
  O3	0.68491(16)	0.43735(12)	−0.02943(10)	1	0.0313(5)
  O4	0.81179(14)	0.06809(10)	0.02407(8)	1	0.0175(4)
  O5	0.92726(15)	−0.01197(11)	−0.04651(9)	1	0.0229(4)
  O6	0.76585(17)	−0.01235(11)	−0.14790(8)	1	0.0213(4)
  O7	0.90141(17)	0.16881(12)	−0.11593(10)	1	0.0289(4)
  O8	0.76172(16)	0.22615(12)	−0.18254(10)	1	0.0294(5)
  O9	0.60916(17)	−0.22805(12)	0.08630(9)	1	0.0220(4)
  H09	0.624(3)	−0.279(2)	0.1042(17)	1	0.05
  C51	0.8226(2)	0.44762(17)	0.18302(13)	1	0.0236(6)
  C52	0.7112(2)	0.45571(16)	0.22623(13)	1	0.0224(6)
  H52	0.721	0.5059	0.2581	1	0.027
  C53	0.6023(2)	0.47238(16)	0.18092(13)	1	0.0224(5)
  H53A	0.612	0.4418	0.1364	1	0.027
  H53B	0.5323	0.4483	0.2042	1	0.027
  C54	0.5820(2)	0.56740(17)	0.16673(12)	1	0.0207(5)
  O51	0.84243(18)	0.51249(12)	0.14213(10)	1	0.0327(5)
  O52	0.88827(16)	0.38509(12)	0.18781(10)	1	0.0289(4)
  O53	0.69947(19)	0.38065(13)	0.26660(10)	1	0.0341(5)
  H53	0.628(3)	0.377(2)	0.2833(17)	1	0.05
  O54	0.48847(17)	0.60192(12)	0.18067(9)	1	0.0274(4)
  O55	0.67121(17)	0.60868(11)	0.14119(9)	1	0.0263(4)
  H55	0.757(3)	0.559(2)	0.1382(16)	1	0.05
  C61	0.4392(3)	0.46918(18)	0.34036(15)	1	0.0321(7)
  H61A	0.3848	0.4648	0.3794	1	0.048
  H61B	0.3981	0.4932	0.3003	1	0.048
  H61C	0.5048	0.5069	0.3529	1	0.048
  O62	0.4827(2)	0.38596(14)	0.32369(11)	1	0.0418(6)
  H62	0.457(3)	0.347(2)	0.3498(17)	1	0.05

• B. X-Ray Powder Diffraction
• The sample was pure, there is no doubt that this is the correct phase. However there is a gap of certain diffraction lines, which would be associated with a variation of unit cell parameters. There may be a change in the rate of hydration for example, to cause such a phenomenon (for view of diagrams and experimental details, see FIG. 2.4.3).
Example 5: Preparation and Analyses of Homoharringtonine Hydrogen (2S,3S)-Tartrate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial (2S,3S-(−)-tartaric acid (unnatural form) according to the general procedure, then isolated as a white prismatic solid mp 202-205° C. (uncorrected) from MeOH. (198.1-203.9, measured by DSC, see FIG. 3.4). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.4)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.81 (s, 1H), 6.75 (s, 1H), 6.10 (d, J=9.5 Hz, 1H), 5.97 (d, J=1.1 Hz, 1H), 5.94 (d, J=1.1 Hz, 1H), 5.34 (s, 1H), 4.36 (s, 2H), 4.18 (d, J=9.6 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 3H), 2.24 (d, J=16.2 Hz, 2H), 1.95 (d, J=16.1 Hz, 1H), 1.16 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR APT* (101 MHz, Methanol-d4) δ 176.81, 174.28, 171.67, 165.24, 149.87, 148.85, 130.83, 126.76, 114.91, 111.89, 102.93, 96.04, 78.34, 76.13, 74.38, 74.10, 71.32, 59.10, 54.28, 53.22, 52.12, 44.80, 44.09, 40.91, 40.46, 29.20, 29.19, 19.95, 19.13. *APT=Attached Proton Test
• IR (Diamond ATR, solid) cm ⁻¹ 3502, 3048, 2971, 2884, 2051, 1981, 1765, 1736, 1656, 1592, 1506, 1490, 1432, 1375, 1348, 1321, 1295, 1265, 1227, 1205, 1165, 1147, 1111, 1081, 1031, 984, 939, 921, 887, 866, 831, 810, 727, 691, 675, 615, 564, 510, 477. See FIG. 1.4
• IR (Diamond ATR, film) cm ⁻¹ 3419, 2963, 1741, 1656, 1611, 1506, 1489, 1440, 1373, 1265, 1224, 1168, 1118, 1083, 1035, 983, 928, 674, 614, 512, 477. See FIG. 1.4
• X-Ray Crystallographic Studies
• A. Single Crystal X-Ray Diffraction (See FIGS. 2.5.1 and 2.5.2)
• From a suspension in its mother liquor, a suitable single crystal of size 0.35×0.28×0.19 mm was finally selected and implemented on the diffractometer.

• 	Structural data
  	Empirical formula	33H45N O15
  	Extended formula	C33H45N1 O15
  	Formula weight	695.7
  	Temperature	150(2)K

  Wavelength

  0.71073

  Å

  	Crystal system, space group	orthorhombic, P 21 21 21
  	Unit cell dimensions	a = 10.7962(3) Å, α = 90°
  		b = 16.3649(5) Å, β = 90°
  		c = 18.6773(5) Å, γ = 90°

  Volume

  3299.88(16)

  Å3

  Z, Calculated density

  4, 1.4 (g · cm−1)

  Absorption coefficient

  0.111

  mm−1

  	F(000)	1480
  	Crystal size	0.35 × 0.28 × 0.19 mm
  	Crystal color	colourless
  	Theta range for data collection	3.12 to 27.48°
  	h_min, h_max	−14, 14
  	k_min, k_max	−18, 21
  	l_min, l_max	−23, 24
  	Reflections collected/unique	53493/4200 [aR(int) = 0.0357]
  	Reflections [I > 2σ]	4022
  	Completeness to theta_max	0.997
  	Absorption correction type	multi-scan
  	Max. and min. transmission	0.979, 0.921
  	Refinement method	Full-matrix least-squares on F2
  	Data/restraints/parameters	4200/0/464
  	bGoodness-of-fit	1.044
  	Final R indices [I > 2σ]:	cR1 = 0.0289, dwR2 = 0.0766
  	R indices (all data):	cR1 = 0.0308, dwR2 = 0.0781
  	Largest diff, peak and hole:	0.245 and −0.156 e.Å−3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
  Atom numbering of FIG. 2.5.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.60365(16)	0.56010(10)	0.77843(9)	1	0.0207(3)
  H1	0.6286	0.5375	0.7338	1	0.025
  C2	0.59199(16)	0.51759(10)	0.83901(9)	1	0.0204(3)
  C3	0.54863(14)	0.56685(9)	0.90214(8)	1	0.0173(3)
  H3	0.4655	0.5475	0.9185	1	0.021
  C4	0.53958(14)	0.65545(9)	0.87170(8)	1	0.0159(3)
  H4	0.4499	0.6705	0.8739	1	0.019
  C5	0.57198(15)	0.64844(10)	0.79030(9)	1	0.0176(3)
  C6	0.46897(15)	0.68171(10)	0.74191(8)	1	0.0209(3)
  H6A	0.4358	0.7336	0.7612	1	0.025
  H6B	0.4003	0.6418	0.738	1	0.025
  C7	0.52972(18)	0.69568(12)	0.66864(9)	1	0.0279(4)
  H7A	0.4941	0.7444	0.6449	1	0.034
  H7B	0.5177	0.6476	0.6372	1	0.034
  C8	0.66784(17)	0.70863(10)	0.68489(9)	1	0.0232(3)
  H8A	0.7186	0.6657	0.6617	1	0.028
  H8B	0.6957	0.7627	0.6674	1	0.028
  N9	0.67903(13)	0.70357(8)	0.76564(7)	1	0.0175(3)
  H9	0.667(3)	0.7517(18)	0.7806(16)	1	0.05
  C10	0.80715(16)	0.68107(11)	0.78842(9)	1	0.0233(3)
  H10A	0.8653	0.7246	0.7736	1	0.028
  H10B	0.8321	0.6299	0.7641	1	0.028
  C11	0.81574(15)	0.66918(10)	0.86982(9)	1	0.0211(3)
  H11A	0.7888	0.613	0.8818	1	0.025
  H11B	0.9033	0.6749	0.8847	1	0.025
  C12	0.73790(14)	0.72935(10)	0.91171(9)	1	0.0183(3)
  C13	0.60770(14)	0.72158(9)	0.91235(8)	1	0.0160(3)
  C14	0.53534(15)	0.77926(9)	0.94934(8)	1	0.0177(3)
  H14	0.4476	0.7753	0.9498	1	0.021
  C15	0.59463(16)	0.84150(10)	0.98478(9)	1	0.0203(3)
  C16	0.72235(16)	0.84894(10)	0.98391(9)	1	0.0228(3)
  C17	0.79564(15)	0.79481(11)	0.94736(9)	1	0.0215(3)
  H17	0.8831	0.8013	0.9461	1	0.026
  C18	0.64308(19)	0.95977(12)	1.03596(11)	1	0.0325(4)
  H18A	0.6364	1.0053	1.0012	1	0.039
  H18B	0.6407	0.9827	1.085	1	0.039
  C19	0.6668(2)	0.39314(10)	0.79407(10)	1	0.0279(4)
  H19A	0.7405	0.4221	0.7771	1	0.042
  H19B	0.6068	0.3884	0.7549	1	0.042
  H19C	0.6903	0.3384	0.8106	1	0.042
  C21	0.60705(15)	0.51652(9)	1.01819(8)	1	0.0167(3)
  C22	0.72136(14)	0.50930(9)	1.06633(8)	1	0.0166(3)
  C23	0.77327(15)	0.59411(9)	1.08420(9)	1	0.0192(3)
  H23A	0.8471	0.5876	1.1151	1	0.023
  H23B	0.8004	0.6208	1.0393	1	0.023
  C24	0.68149(16)	0.64899(10)	1.12155(9)	1	0.0217(3)
  C25	0.6586(2)	0.76969(15)	1.18925(17)	1	0.0533(7)
  H25A	0.6067	0.7412	1.2243	1	0.08
  H25B	0.6057	0.7964	1.1536	1	0.08
  H25C	0.709	0.8109	1.2137	1	0.08
  C31	0.82188(15)	0.46027(9)	1.02660(9)	1	0.0191(3)
  H31A	0.8479	0.4917	0.9839	1	0.023
  H31B	0.8949	0.4551	1.0583	1	0.023
  C32	0.78268(16)	0.37451(9)	1.00245(9)	1	0.0197(3)
  H32A	0.7604	0.3411	1.0447	1	0.024
  H32B	0.709	0.3784	0.9711	1	0.024
  C33	0.88905(17)	0.33394(10)	0.96190(10)	1	0.0233(3)
  H33A	0.9647	0.3386	0.9916	1	0.028
  H33B	0.9038	0.3655	0.9175	1	0.028
  C34	0.87253(17)	0.24391(10)	0.94135(9)	1	0.0230(3)
  C35	0.98538(19)	0.21661(13)	0.89846(13)	1	0.0370(5)
  H35A	0.9902	0.2482	0.854	1	0.055
  H35B	0.9779	0.1584	0.8871	1	0.055
  H35C	1.0605	0.2258	0.9268	1	0.055
  C36	0.8548(2)	0.18850(12)	1.00617(11)	1	0.0385(5)
  H36A	0.8438	0.132	0.9901	1	0.058
  H36B	0.7814	0.2059	1.0329	1	0.058
  H36C	0.9279	0.192	1.0372	1	0.058
  O1	0.61196(13)	0.43788(7)	0.85237(7)	1	0.0255(3)
  O2	0.54324(13)	0.90276(8)	1.02592(7)	1	0.0284(3)
  O3	0.75632(13)	0.91539(8)	1.02482(7)	1	0.0320(3)
  O4	0.63780(10)	0.56087(7)	0.95949(6)	1	0.0183(2)
  O5	0.50856(11)	0.48612(7)	1.02953(7)	1	0.0244(3)
  O6	0.69079(12)	0.46715(7)	1.13040(6)	1	0.0221(2)
  HO6	0.616(3)	0.4684(17)	1.1363(15)	1	0.05
  O7	0.57142(13)	0.64049(9)	1.12151(10)	1	0.0408(4)
  O8	0.73882(13)	0.71156(8)	1.15402(8)	1	0.0352(3)
  O9	0.76355(13)	0.23916(8)	0.89708(8)	1	0.0302(3)
  HO9	0.751(3)	0.1897(18)	0.8886(15)	1	0.05
  C51	0.69752(17)	1.00450(11)	0.84160(9)	1	0.0240(3)
  C52	0.75591(16)	0.92992(10)	0.80382(9)	1	0.0216(3)
  H52	0.8202	0.9054	0.8358	1	0.026
  C53	0.81501(17)	0.95062(11)	0.73116(9)	1	0.0248(3)
  H53	0.7586	0.9885	0.7048	1	0.03
  C54	0.94378(18)	0.99098(12)	0.73715(10)	1	0.0291(4)
  O51	0.76283(13)	1.06995(8)	0.84564(8)	1	0.0331(3)
  O52	0.59210(13)	0.99642(8)	0.86509(8)	1	0.0337(3)
  O53	0.65877(13)	0.87221(7)	0.79311(7)	1	0.0276(3)
  HO53	0.604(3)	0.8924(17)	0.8176(15)	1	0.05
  O54	0.82858(17)	0.87829(10)	0.69067(9)	1	0.0424(4)
  HO54	0.905(3)	0.8812(18)	0.6760(15)	1	0.05
  O55	1.02589(15)	0.96663(11)	0.69804(9)	1	0.0465(4)
  O56	0.95769(14)	1.05015(9)	0.78265(9)	1	0.0373(3)
  HO56	0.868(3)	1.0629(17)	0.8111(14)	1	0.05

• B. X-Ray Powder Diffraction
• The sample was pure. There was a very good match between the experimental pattern and the calculated pattern (for view of diagrams and experimental details, see FIG. 2.5.3).
Example 6: Preparation and Analyses of Homoharringtonine Hydrogen (2R,3R)-Tartrate (Diastemomer of Example 5)
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial (+)-(2R,3R)-tartaric acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 206-208° C. (uncorrected) from MeOH. (204.6-208.5, measured by DSC, see FIG. 3.5). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.5)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.80 (s, 1H), 6.75 (s, 1H), 6.10 (d, J=9.7 Hz, 1H), 5.97 (d, J=1.0 Hz, 1H), 5.94 (d, J=1.1 Hz, 1H), 5.34 (s, 1H), 4.36 (s, 2H), 4.18 (d, J=9.6 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 3H), 3.44-3.32 (m, 2H), 3.28-3.16 (m, 1H), 2.69 (dd, J=13.7, 5.9 Hz, 1H), 2.27-2.21 (m, 2H), 2.21-1.97 (m, 2H), 1.95 (d, J=16.1 Hz, 1H), 1.49-1.18 (m, 6H), 1.16 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR APT* (101 MHz, Methanol-d₄) δ 176.80, 174.24, 171.62, 165.20, 149.84, 148.83, 130.81, 126.73, 114.86, 111.85, 102.89, 96.00, 78.29, 76.09, 74.34, 74.07, 71.28, 59.05, 54.22, 53.18, 52.07, 44.76, 44.05, 40.87, 40.43, 29.23, 29.17, 29.15, 19.91, 19.10. *APT=Attached Proton Test
• IR (Diamond ATR, solid) cm ⁻¹ 3491, 3044, 2969, 1762, 1737, 1654, 1587, 1506, 1489, 1464, 1431, 1375, 1320, 1295, 1259, 1229, 1210, 1172, 1149, 1107, 1082, 1028, 984, 940, 924, 866, 819, 804, 735, 690, 616, 565, 512, 476. See FIG. 1.5
• IR (Diamond ATR, film) cm ⁻¹ 3417, 2963, 1741, 1655, 1611, 1505, 1489, 1440, 1373, 1265, 1223, 1167, 1118, 1082, 1034, 983, 928, 769, 675, 614, 565, 510, 478, 0, 1031, 984, 939, 921, 887, 866, 831, 810, 727, 691, 675, 615, 564, 510. See FIG. 1.5
• X-Ray Crystallographic Studies
• A. Single Crystal X-Ray Diffraction (See FIGS. 2.6.1 and 2.6.2)
• From a suspension in its mother liquor, a suitable single crystal of size 0.54×0.41×0.34 mm was finally selected and implemented on the diffractometer.

• Structural data

  Empirical formula	C33H45NO15
  Extended formula	C29H40NO9, C4H5O6
  Formula weight	695.7
  Temperature	150(2) K
  Wavelength	0.71073 Å
  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions:	a = 10.6770(3) Å, α = 90°
  	b = 16.6169(6) Å, β = 90°
  	c = 18.7442(7) Å, γ = 90°
  Volume	3325.6(2) Å3
  Z, Calculated density	4, 1.39 (g · cm−1)
  Absorption coefficient	0.110 mm−1
  F(000)	1480
  Crystal size	0.54 × 0.41 × 0.34 mm
  Crystal color	colourless
  Theta range for data collection	3.11 to 27.48°
  h_min, h_max	−13, 10
  k_min, k_max	−21, 19
  l_min, l_max	−23, 15
  Reflections collected/unique	15282/4165 [aR(int) = 0.0328]
  Reflections [I > 2σ]	3523
  Completeness to theta_max	0.979
  Absorption correction type	multi-scan
  Max. and min. transmission	0.963, 0.891
  Refinement method	Full-matrix least-squares on F2
  Data/restraints/parameters	4165/0/458
  bGoodness-of-fit	1.021
  Final R indices [I > 2σ]:	cR1 = 0.0368, dwR2 = 0.0759
  R indices (all data):	cR1 = 0.0498, dwR2 = 0.0816
  Largest diff. peak and hole	0.23 and −0.195 e · Å−3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIG. 2.6.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.8908(2)	0.06521(13)	0.73105(13)	1	0.0187(5)
  H1	0.8694	0.0434	0.7763	1	0.022
  C2	0.9037(2)	0.02207(13)	0.67131(13)	1	0.0194(5)
  C3	0.9421(2)	0.06998(13)	0.60762(12)	1	0.0170(5)
  H3	1.0267	0.0525	0.5907	1	0.02
  C4	0.94749(19)	0.15799(13)	0.63555(12)	1	0.0149(5)
  H4	1.0376	0.1742	0.6331	1	0.018
  C5	0.91467(19)	0.15286(12)	0.71688(12)	1	0.0164(5)
  C6	1.0130(2)	0.19306(14)	0.76376(13)	1	0.0210(5)
  H6A	1.0399	0.2449	0.7427	1	0.025
  H6B	1.0873	0.1579	0.7691	1	0.025
  C7	0.9504(2)	0.20687(17)	0.83590(14)	1	0.0310(6)
  H7A	0.9805	0.2574	0.858	1	0.037
  H7B	0.9677	0.1616	0.8688	1	0.037
  C8	0.8100(2)	0.21218(14)	0.81897(12)	1	0.0218(5)
  H8A	0.7635	0.1686	0.8434	1	0.026
  H8B	0.7756	0.2646	0.8345	1	0.026
  N9	0.80013(17)	0.20331(11)	0.73928(10)	1	0.0167(4)
  H9	0.808(3)	0.2532(19)	0.7212(17)	1	0.05
  C10	0.6742(2)	0.17363(14)	0.71581(13)	1	0.0212(5)
  H10A	0.609	0.2121	0.7316	1	0.025
  H10B	0.6569	0.1211	0.7386	1	0.025
  C11	0.6677(2)	0.16426(14)	0.63473(13)	1	0.0200(5)
  H11A	0.6969	0.1096	0.622	1	0.024
  H11B	0.5792	0.1689	0.6196	1	0.024
  C12	0.7446(2)	0.22516(13)	0.59340(13)	1	0.0178(5)
  C13	0.87646(19)	0.22060(12)	0.59378(12)	1	0.0142(5)
  C14	0.9478(2)	0.27752(13)	0.55633(12)	1	0.0176(5)
  H14	1.0367	0.2753	0.5567	1	0.021
  C15	0.8861(2)	0.33632(13)	0.51922(13)	1	0.0188(5)
  C16	0.7568(2)	0.34102(14)	0.51918(13)	1	0.0229(5)
  C17	0.6842(2)	0.28758(13)	0.55610(13)	1	0.0210(5)
  H17	0.5955	0.2924	0.5566	1	0.025
  C18	0.8325(3)	0.44907(16)	0.46298(16)	1	0.0358(7)
  H18A	0.8347	0.4683	0.413	1	0.043
  H18B	0.8367	0.4963	0.4951	1	0.043
  C19	0.8337(2)	−0.10152(13)	0.71742(14)	1	0.0278(6)
  H19A	0.8918	−0.1024	0.7579	1	0.042
  H19B	0.8166	−0.1568	0.702	1	0.042
  H19C	0.7552	−0.0756	0.7319	1	0.042
  C21	0.8802(2)	0.01342(12)	0.49504(13)	1	0.0172(5)
  C22	0.7657(2)	0.00350(13)	0.44714(12)	1	0.0171(5)
  C23	0.7075(2)	0.08447(12)	0.42747(13)	1	0.0185(5)
  H23A	0.637	0.0752	0.3942	1	0.022
  H23B	0.6731	0.1097	0.4711	1	0.022
  C24	0.7990(2)	0.14152(13)	0.39345(13)	1	0.0203(5)
  C25	0.8218(2)	0.26011(16)	0.32546(17)	1	0.0354(7)
  H25A	0.8661	0.2903	0.3626	1	0.053
  H25B	0.7713	0.2972	0.2968	1	0.053
  H25C	0.8828	0.2329	0.2947	1	0.053
  C32	0.6115(2)	−0.17869(13)	0.54608(14)	1	0.0218(5)
  H32A	0.5368	−0.179	0.5147	1	0.026
  H32B	0.5885	−0.1491	0.59	1	0.026
  C37	0.7146(2)	−0.13192(12)	0.50853(13)	1	0.0197(5)
  H37A	0.7423	−0.1619	0.4657	1	0.024
  H37B	0.7874	−0.1262	0.5409	1	0.024
  C38	0.6679(2)	−0.04831(12)	0.48638(13)	1	0.0192(5)
  H38A	0.6402	−0.0191	0.5296	1	0.023
  H38B	0.594	−0.0549	0.455	1	0.023
  C42	0.6411(2)	−0.26590(13)	0.56665(13)	1	0.0214(5)
  C44	0.5296(2)	−0.30128(16)	0.60626(15)	1	0.0310(6)
  H44A	0.5486	−0.3567	0.6205	1	0.047
  H44B	0.456	−0.301	0.575	1	0.047
  H44C	0.5122	−0.2689	0.6488	1	0.047
  C45	0.6740(3)	−0.31800(14)	0.50279(15)	1	0.0351(7)
  H45A	0.7474	−0.2955	0.4785	1	0.053
  H45B	0.603	−0.3193	0.4697	1	0.053
  H45C	0.6928	−0.3728	0.5189	1	0.053
  O1	0.88885(17)	−0.05711(9)	0.65947(9)	1	0.0254(4)
  O2	0.93569(16)	0.39596(10)	0.47637(9)	1	0.0273(4)
  O3	0.71970(17)	0.40404(11)	0.47595(10)	1	0.0334(4)
  O4	0.85067(13)	0.06035(9)	0.55137(8)	1	0.0176(3)
  O5	0.97892(14)	−0.01899(9)	0.48520(9)	1	0.0250(4)
  O6	0.80450(16)	−0.03582(10)	0.38304(9)	1	0.0231(4)
  HO6	0.878(3)	−0.0464(19)	0.3873(17)	1	0.05
  O7	0.91117(15)	0.13633(11)	0.39748(11)	1	0.0374(5)
  O8	0.74109(15)	0.20093(9)	0.35831(10)	1	0.0275(4)
  O9	0.74716(17)	−0.26262(10)	0.61420(11)	1	0.0320(5)
  HO9	0.755(3)	−0.307(2)	0.6285(18)	1	0.05
  C51	0.5651(2)	0.49263(15)	0.76865(15)	1	0.0299(6)
  C52	0.6393(2)	0.42749(13)	0.72898(15)	1	0.0237(5)
  H52	0.6068	0.4235	0.6791	1	0.028
  C53	0.7815(2)	0.44249(13)	0.72627(14)	1	0.022
  H53	0.8101	0.4609	0.7744	1	0.026
  C54	0.8215(2)	0.50558(14)	0.67017(14)	1	0.0241(5)
  O51	0.5872(2)	0.56776(10)	0.75398(12)	1	0.0416(5)
  HO51	0.663(3)	0.5688(18)	0.7178(18)	1	0.05
  O52	0.48857(19)	0.47183(12)	0.81317(11)	1	0.0462(6)
  O53	0.61742(18)	0.35372(10)	0.76410(12)	1	0.0383(5)
  HO53	0.566(3)	0.361(2)	0.7939(18)	1	0.05
  O54	0.84448(16)	0.36948(10)	0.70908(10)	1	0.0275(4)
  HO54	0.887(3)	0.3812(19)	0.6718(18)	1	0.05
  O55	0.90625(17)	0.48767(11)	0.62938(10)	1	0.0342(4)
  O56	0.76291(16)	0.57314(9)	0.67107(11)	1	0.0323(4)

• A. X-Ray Powder Diffraction
• The sample was pure and there was a very good match between the experimental pattern and the calculated pattern (for view of diagrams and experimental details, see FIG. 2.6.3).
Example 7: Preparation and Analyses of Homoharringtonine Hydrogen (2′″S)-Citramalate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial (2S)-citramalic acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 195.9-198.9° C. (measured by DSC, see FIG. 3.6). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.6)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.80 (s, 1H), 6.74 (s, 1H), 6.09 (d, J=9.6 Hz, 1H), 5.96 (d, J=0.9 Hz, 1H), 5.93 (d, J=0.9 Hz, 1H), 5.33 (s, 1H), 4.17 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 3.54 (s, 3H), 3.45-3.31 (m, 2H), 3.19 (dd, J=10.6, 6.9 Hz, 1H), 2.70 (d, J=15.7 Hz, 2H), 2.63 (d, J=15.7 Hz, 1H), 2.26-2.12 (m, 4H), 1.94 (d, J=16.1 Hz, 2H), 1.45-1.29 (m, 9H), 1.29-1.17 (m, 1H), 1.15 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR (101 MHz, MeOD) δ 181.21, 176.08, 174.23, 171.62, 165.18, 149.81, 148.79, 130.84, 126.78, 114.87, 114.58, 111.53, 102.58, 95.71, 78.24, 76.08, 74.03, 73.18, 71.27, 58.75, 53.91, 52.90, 51.79, 48.63, 46.32, 44.47, 43.77, 40.59, 40.15, 28.94, 28.89, 28.87, 26.22, 19.62, 18.80.
• IR (Diamond ATR, solid) cm⁻¹ 2965, 1759, 1739, 1710, 1651, 1506, 1489, 1371, 1341, 1225, 1162, 1079, 1033, 972, 944, 925, 885, 866, 830, 786, 714, 690, 643, 615, 584, 562, 511. See FIG. 1.6
• IR (Diamond ATR, film) cm ⁻¹ 3434, 2968, 1744, 1656, 1590, 1505, 1490, 1374, 1265, 1224, 1166, 1084, 1033, 930, 710, 565. See FIG. 1.6
• X-Ray Powder Diffraction
• The powder sample is well crystallised, with a peak width of 0.102° (2θ) at 17.597° (2θ) (for view of diagrams and experimental details, see FIG. 2.7.1).
Example 8: Preparation and Analyses of Homoharringtonine Hydrogen (2′″R)-Citramalate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial (2R)-citramalic acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 202.7-204.7° C. (measured by DSC, see FIG. 3.7). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.7)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.79 (s, 1H), 6.74 (s, 1H), 6.08 (d, J=9.6 Hz, 1H), 5.95 (d, J=1.0 Hz, 1H), 5.93 (d, J=1.0 Hz, 1H), 5.33 (s, 1H), 4.17 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 3.54 (s, 3H), 3.43-3.31 (m, 2H), 3.22-3.14 (m, 1H), 2.73-2.66 (m, 2H), 2.63 (d, J=15.7 Hz, 1H), 2.23 (d, J=16.0 Hz, 2H), 2.19 (s, 1H), 1.94 (d, J=16.1 Hz, 1H), 1.44-1.29 (m, 8H), 1.29-1.17 (m, 1H), 1.15 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR APT* (101 MHz, Methanol-d₄) δ 181.21, 176.08, 174.23, 171.62, 165.18, 149.81, 148.79, 130.84, 126.78, 114.87, 111.82, 102.87, 96.00, 78.24, 76.08, 74.33, 73.18, 71.27, 59.04, 54.21, 53.20, 52.07, 48.94, 46.62, 44.76, 44.05, 40.87, 40.45, 29.23, 29.19, 29.17, 26.50, 19.92, 19.09. *APT=Attached Proton Test
• IR (Diamond ATR, solid) cm ⁻¹ 3681, 3512, 2969, 2845, 1764, 1740, 1707, 1652, 1605, 1513, 1495, 1469, 1440, 1369, 1332, 1292, 1260, 1227, 1204, 1167, 1147, 1124, 1080, 1048, 1033, 1023, 991, 971, 930, 885, 869, 824, 786, 753, 718, 689, 676, 644, 614, 564, 512, 475. See FIG. 1.7
• IR (Diamond ATR, film) cm ⁻¹ 3434, 2968, 2845, 1742, 1655, 1582, 1506, 1490, 1458, 1374, 1265, 1224, 1166, 1084, 1047, 1033, 930, 831, 710, 565, 476. See FIG. 1.7
• X-Ray Crystallographic Studies
• A. Single Crystal X-Ray Diffraction (See FIGS. 2.8.1 and 2.8.2)
• From a suspension in its mother liquor, a suitable single crystal of size 0.44×0.32×0.16 mm was finally selected and implemented on the diffractometer.

• Structural data

  Empirical formula	C34H47NO14
  Extended formula	C29H40NO9, C5H7O5
  Formula weight	693.73
  Temperature	150(2) K
  Wavelength	0.71073 Å
  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions	a = 10.3550(3) Å, α = 90°
  	b = 17.0899(6) Å, β = 90°
  	c = 19.2854(7) Å, γ = 90°
  Volume	3412.9(2) Å3
  Z, Calculated density	4, 1.35 (g · cm−1)
  Absorption coefficient	0.105 mm−1
  F(000)	1480
  Crystal size	0.44 × 0.32 × 0.16 mm
  Crystal color	colourless
  Theta range for data collection	3.09 to 27.48°
  h_min, h_max	−13, 13
  k_min, k_max	−22, 20
  l_min, l_max	−19, 25
  Reflections collected/unique	16497/7790 [aR(int) = 0.0336]
  Reflections [I > 2σ]	6790
  Completeness to theta_max	0.996
  Absorption correction type	multi-scan
  Max. and min. transmission	0.983, 0.880
  Refinement method	Full-matrix least-squares on F2
  Data/restraints/parameters	7790/0/462
  bGoodness-of-fit	1.026
  Final R indices[I > 2σ]	cR1 = 0.0413, dwR2 = 0.0899
  R indices (all data)	cR1 = 0.0508, dwR2 = 0.0948
  Largest diff. peak and hole	0.403 and −0.199 e · Å −3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIG. 2.8.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.11571(16)	0.05636(10)	0.26511(9)	1	0.0175(4)
  H1	0.1363	0.0342	0.2213	1	0.021
  C2	0.09856(16)	0.01523(10)	0.32323(9)	1	0.0171(4)
  C3	0.06120(16)	0.06351(11)	0.38472(9)	1	0.0162(3)
  H3	−0.0279	0.0492	0.4002	1	0.019
  C4	0.06272(15)	0.14871(10)	0.35705(9)	1	0.0143(3)
  H4	−0.0287	0.1675	0.3589	1	0.017
  C5	0.09821(15)	0.14231(10)	0.27823(9)	1	0.0159(4)
  C6	0.00002(16)	0.18455(11)	0.23179(9)	1	0.0195(4)
  H6A	−0.0761	0.1508	0.2234	1	0.023
  H6B	−0.0293	0.2336	0.254	1	0.023
  C7	0.06914(19)	0.20226(14)	0.16369(10)	1	0.0282(5)
  H7A	0.0457	0.255	0.1465	1	0.034
  H7B	0.046	0.1632	0.1279	1	0.034
  C8	0.21369(17)	0.19809(11)	0.18060(9)	1	0.0190(4)
  H8A	0.2545	0.153	0.1569	1	0.023
  H8B	0.2581	0.2467	0.166	1	0.023
  N9	0.22010(13)	0.18836(9)	0.25825(7)	1	0.0156(3)
  HN9	0.215(2)	0.2413(15)	0.2762(14)	1	0.05
  C10	0.34708(16)	0.15611(11)	0.28115(9)	1	0.0187(4)
  H10A	0.4167	0.193	0.2681	1	0.022
  H10B	0.3634	0.1059	0.2571	1	0.022
  C11	0.35010(16)	0.14274(11)	0.35966(9)	1	0.0182(4)
  H11A	0.313	0.0906	0.3698	1	0.022
  H11B	0.4411	0.1423	0.3753	1	0.022
  C12	0.27690(16)	0.20378(10)	0.40075(9)	1	0.0161(3)
  C13	0.14095(15)	0.20673(10)	0.39833(9)	1	0.0142(3)
  C14	0.07316(17)	0.26533(10)	0.43397(9)	1	0.0168(4)
  H14	−0.0183	0.2688	0.4315	1	0.02
  C15	0.14387(18)	0.31747(10)	0.47263(9)	1	0.0200(4)
  C16	0.27616(18)	0.31308(11)	0.47618(9)	1	0.0207(4)
  C17	0.34575(17)	0.25856(11)	0.43994(9)	1	0.0190(4)
  H17	0.4374	0.258	0.4414	1	0.023
  C18	0.2137(2)	0.41952(12)	0.53342(11)	1	0.0334(5)
  H18A	0.2207	0.4679	0.5055	1	0.04
  H18B	0.2103	0.4343	0.583	1	0.04
  C19	0.1546(2)	−0.10852(11)	0.27911(11)	1	0.0300(5)
  H19A	0.0911	−0.1088	0.2414	1	0.045
  H19B	0.1691	−0.1622	0.2952	1	0.045
  H19C	0.2361	−0.0864	0.2622	1	0.045
  C21	0.11247(16)	0.01321(10)	0.49827(9)	1	0.0161(3)
  C22	0.22813(16)	0.00398(10)	0.54736(9)	1	0.0178(4)
  C23	0.29449(17)	0.08219(10)	0.56296(10)	1	0.0189(4)
  H23A	0.369	0.0729	0.594	1	0.023
  H23B	0.3277	0.1048	0.5192	1	0.023
  C24	0.20436(17)	0.13941(10)	0.59644(10)	1	0.0196(4)
  C25	0.18690(19)	0.25170(12)	0.66695(12)	1	0.0293(5)
  H25A	0.1478	0.2853	0.6315	1	0.044
  H25B	0.2392	0.2837	0.6984	1	0.044
  H25C	0.1187	0.2253	0.6933	1	0.044
  C31	0.32662(17)	−0.05075(11)	0.51274(10)	1	0.0204(4)
  H31A	0.361	−0.0244	0.4709	1	0.025
  H31B	0.3997	−0.0586	0.5451	1	0.025
  C32	0.27492(18)	−0.13115(11)	0.49143(10)	1	0.0222(4)
  H32A	0.2495	−0.1609	0.5333	1	0.027
  H32B	0.1973	−0.1245	0.462	1	0.027
  C33	0.37715(18)	−0.17662(11)	0.45161(11)	1	0.0248(4)
  H33A	0.4587	−0.1741	0.4783	1	0.03
  H33B	0.3923	−0.1495	0.407	1	0.03
  C34	0.34851(18)	−0.26269(11)	0.43594(11)	1	0.0240(4)
  C36	0.4577(2)	−0.29453(13)	0.39087(14)	1	0.0423(6)
  H36A	0.4411	−0.3497	0.3801	1	0.063
  H36B	0.5397	−0.2899	0.4159	1	0.063
  H36C	0.4623	−0.2644	0.3477	1	0.063
  C35	0.3354(2)	−0.31160(13)	0.50108(12)	1	0.0363(5)
  H35A	0.2616	−0.2929	0.5283	1	0.054
  H35B	0.4144	−0.3071	0.5288	1	0.054
  H35C	0.3216	−0.3665	0.4884	1	0.054
  O1	0.10699(13)	−0.06191(7)	0.33525(7)	1	0.0244(3)
  O2	0.32223(14)	0.37011(8)	0.52078(7)	1	0.0304(3)
  O3	0.09930(13)	0.37738(8)	0.51464(7)	1	0.0288(3)
  O4	0.15171(11)	0.05193(7)	0.44075(6)	1	0.0171(3)
  O5	0.00628(12)	−0.01257(8)	0.50746(7)	1	0.0222(3)
  O6	0.18733(13)	−0.03191(8)	0.60999(7)	1	0.0221(3)
  HO6	0.120(3)	−0.0138(16)	0.6222(14)	1	0.05
  O7	0.08889(13)	0.13801(9)	0.59158(9)	1	0.0357(4)
  O8	0.26816(12)	0.19381(8)	0.63389(7)	1	0.0243(3)
  O9	0.22961(14)	−0.26485(9)	0.39752(9)	1	0.0348(4)
  HO9	0.203(3)	−0.3138(17)	0.3982(14)	1	0.05
  C51	0.17383(18)	0.50529(11)	0.36479(10)	1	0.0247(4)
  C52	0.31671(18)	0.48833(12)	0.35581(12)	1	0.0299(5)
  H52A	0.3411	0.4469	0.3892	1	0.036
  H52B	0.3654	0.5361	0.3686	1	0.036
  C53	0.36065(18)	0.46262(12)	0.28366(12)	1	0.0288(5)
  C54	0.2995(2)	0.51004(15)	0.22598(13)	1	0.0470(6)
  H54A	0.3131	0.5659	0.2348	1	0.071
  H54B	0.2067	0.4991	0.2242	1	0.071
  H54C	0.3392	0.4958	0.1816	1	0.071
  C55	0.33695(18)	0.37452(11)	0.26995(10)	1	0.0243(4)
  O51	0.13621(14)	0.56592(9)	0.39014(9)	1	0.0361(4)
  O52	0.09277(13)	0.45011(9)	0.34618(8)	1	0.0300(3)
  HO52	0.147(2)	0.4107(15)	0.3218(14)	1	0.05
  O53	0.49802(14)	0.47478(10)	0.28234(10)	1	0.0438(4)
  HO53	0.530(2)	0.4274(17)	0.2667(14)	1	0.05
  O54	0.42729(14)	0.33586(9)	0.24647(8)	1	0.0368(4)
  O55	0.22436(12)	0.34821(8)	0.28413(7)	1	0.0261(3)

• A. X-Ray Powder Diffraction
• The sample was pure and well crystallised, with a peak width of 0.107° (2θ) at 16.992° (2θ). There was a very good match between the experimental pattern and the calculated pattern (for view of diagrams and experimental details, see FIG. 2.8.3).
Example 9: Preparation and Analyses of Homoharringtonine Hydrogen Succinate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial succinic acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 158.1-160.0° C. (measured by DSC, see FIG. 3.8).
• DSC Analysis (See FIG. 3.8)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.77 (s, 1H), 6.71 (s, 1H), 6.07 (dd, J=9.6, 0.7 Hz, 1H), 5.95 (d, J=1.1 Hz, 1H), 5.92 (d, J=1.1 Hz, 1H), 5.31 (d, J=0.6 Hz, 1H), 4.12 (d, J=9.6 Hz, 1H), 3.79 (s, 3H), 3.54 (s, 3H), 2.49 (s, 4H), 2.22 (d, J=16.2 Hz, 1H), 1.93 (d, J=16.1 Hz, 2H), 1.15 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³ C NMR APT* (101 MHz, D₂O) δ 179.49, 174.22, 171.93, 162.89, 147.84, 146.75, 129.74, 125.23, 113.38, 111.12, 101.62, 95.53, 76.99, 75.26, 73.68, 71.33, 58.41, 52.95, 52.23, 51.27, 48.86, 47.58, 42.72, 42.55, 39.19, 38.77, 31.20, 27.59, 18.59, 17.69. *APT=Attached Proton Test
• IR (KBr, solid), cm⁻¹ 3571.1, 3375.3, 3083.4, 2964.4, 1755.4, 1736.7, 1661.8, 1575.5, 1504.8, 1489.7, 1375.0, 1346.3, 1326.1, 1267.2, 1227.1, 1188.3, 1151.7, 1083.4, 1034.7, 929.4, 859.4, 802.8, 758.1, 709.9, 658.9, 617.9, 561.2, 510.6. See FIG. 1.8
Example 10: Preparation and Analyses of (3S,4S,5R,2′R)-Homoharringtonine Hydrogen Itaconate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial itaconic acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 178.3-181.2° C. (measured by DSC, see FIG. 3.9). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.9)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.78 (s, 1H), 6.72 (s, 1H), 6.08 (d, J=9.6 Hz, 1H), 6.01 (d, J=1.7 Hz, 1H), 5.95 (d, J=1.1 Hz, 1H), 5.92 (d, J=1.1 Hz, 1H), 5.51 (q, J=1.2 Hz, 1H), 5.32 (s, 1H), 4.14 (d, J=9.6 Hz, 1H), 3.80 (s, 3H), 3.54 (s, 3H), 3.51-3.42 (m, 1H), 3.25-3.07 (m, 2H), 2.72-2.60 (m, 1H), 2.26-2.20 (m, 2H), 2.20-2.07 (m, 2H), 1.94 (d, J=16.1 Hz, 2H), 1.47-1.29 (m, 5H), 1.23 (d, J=10.6 Hz, 1H), 1.15 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR (101 MHz, MeOD)** δ 125.11, 114.53, 111.47, 102.52, 96.09, 74.12, 58.66, 53.95, 53.18, 48.70, 44.48, 43.78, 41.66, 40.59, 40.44, 29.12, 28.94, 28.87, 19.70, 18.81. **DEPT135: Distortionless Enhancement by Polarization Transfer (non-quaternary carbons only)
• IR (Diamond ATR, solid) cm⁻¹ 3473.2, 2968.4, 2899.8, 2564.7, 1760.7, 1733.5, 1657.6, 1569.7, 1506.4, 1488.9, 1436.1, 1374.9, 1348.9, 1264.2, 1240.7, 1226.2, 1185, 1168.8, 1149.8, 1112.1, 1082.4, 1043.1, 1032.9, 1022.2, 982, 928.1, 890, 866.7, 819.8, 772.1, 722.1, 690.1, 616.7, 543. See FIG. 1.9
• IR (ATR, film) cm⁻¹ 3458.8, 2967, 1741.5, 1654.8, 1576.7, 1505.2, 1489.3, 1464.3, 1373.4, 1223.8, 1167, 1083.1, 1033.3, 933.6, 563.4. See FIG. 1.9
• X-Ray Crystallographic Studies
• Single Crystal X-Ray Diffraction (See FIGS. 2.9.1 and 2.9.2)
• From a suspension in its mother liquor, a suitable single crystal of size 0.39×0.22×0.1 mm was finally selected and implemented on the diffractometer.

• Structural data

  Empirical formula	C34H45NO13
  Extended formula	C29H40NO9, C5H5O4
  Formula weight	675.71
  Temperature	150(2) K
  Wavelength	0.71073 Å
  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions	a = 10.9895(4) Å, α = 90°
  	b = 16.1963(6) Å, β = 90°
  	c = 18.7277(5) Å, γ = 90°
  Volume	3333.33(19) Å3
  Z, Calculated density	4, 1.346 (g · cm−1)
  Absorption coefficient	0.103 mm−1
  F(000)	1440
  Crystal size	0.39 × 0.22 × 0.1 mm
  Crystal color	colourless
  Theta range for data collection	3.12 to 27.48°
  h_min, h_max	−11, 14
  k_min, k_max	−13, 20
  l_min, l_max	−16, 24
  Reflections collected/unique	15962/4207 [aR(int) = 0.0449]
  Reflections [I > 2σ]	3444
  Completeness to theta_max	0.986
  Absorption correction type	multi-scan
  Max. and min. transmission	0.990, 0.844
  Refinement method:	Full-matrix least-squares on F2
  Data/restraints/parameters	4207/0/446
  bGoodness-of-fit	1.054
  Final R indices [I > 2σ]	cR1 = 0.0411, dwR2 = 0.0914
  R indices (all data)	cR1 = 0.0557, dwR2 = 0.0986
  Largest diff. peak and hole	0.312 and −0.249 e · Å−3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIG. 2.9.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.4085(2)	0.94954(16)	0.28454(13)	1	0.0246(6)
  H1	0.3897	0.972	0.239	1	0.029
  C2	0.4040(2)	0.99163(16)	0.34531(13)	1	0.0239(5)
  C3	0.4399(2)	0.94237(16)	0.40941(12)	1	0.0206(5)
  H3	0.5169	0.9646	0.4305	1	0.025
  C4	0.4605(2)	0.85392(16)	0.38019(11)	1	0.0187(5)
  H4	0.548	0.8406	0.3893	1	0.022
  C5	0.4471(2)	0.86236(16)	0.29702(12)	1	0.0216(5)
  C6	0.5613(2)	0.83684(18)	0.25641(12)	1	0.0244(6)
  H6A	0.5945	0.7845	0.2755	1	0.029
  H6B	0.6247	0.8801	0.2599	1	0.029
  C7	0.5195(3)	0.8261(2)	0.17935(13)	1	0.0330(7)
  H7A	0.5696	0.7843	0.1544	1	0.04
  H7B	0.5244	0.879	0.153	1	0.04
  C8	0.3878(3)	0.7973(2)	0.18586(13)	1	0.0347(7)
  H8A	0.3332	0.8339	0.1582	1	0.042
  H8B	0.3791	0.7402	0.1675	1	0.042
  N9	0.35665(19)	0.80066(14)	0.26453(10)	1	0.0225(5)
  H9	0.3728	0.749	0.284	1	0.027
  C10	0.2240(2)	0.81867(19)	0.27555(14)	1	0.0293(6)
  H10A	0.1752	0.7717	0.2576	1	0.035
  H10B	0.2013	0.8683	0.2477	1	0.035
  C11	0.1946(2)	0.83313(19)	0.35427(13)	1	0.0280(6)
  H11A	0.2153	0.8908	0.3668	1	0.034
  H11B	0.1061	0.8258	0.3617	1	0.034
  C12	0.2625(2)	0.77534(17)	0.40351(12)	1	0.0218(5)
  C13	0.3876(2)	0.78580(16)	0.41518(12)	1	0.0197(5)
  C14	0.4503(2)	0.73128(16)	0.45992(12)	1	0.0226(5)
  H14	0.5349	0.7378	0.4685	1	0.027
  C15	0.3868(2)	0.66846(18)	0.49096(13)	1	0.0281(6)
  C16	0.2644(2)	0.65757(18)	0.47829(14)	1	0.0300(6)
  C17	0.1998(2)	0.70918(17)	0.43475(13)	1	0.0274(6)
  H17	0.1156	0.7006	0.426	1	0.033
  C18	0.3315(3)	0.5504(2)	0.5409(2)	1	0.0595(10)
  H18A	0.3503	0.5025	0.5101	1	0.071
  H18B	0.3207	0.5305	0.5905	1	0.071
  C19	0.3222(3)	1.11383(18)	0.29761(14)	1	0.0333(7)
  H19A	0.2562	1.0809	0.277	1	0.05
  H19B	0.3856	1.1225	0.2616	1	0.05
  H19C	0.2902	1.1674	0.3132	1	0.05
  C21	0.3633(2)	0.98532(16)	0.52334(12)	1	0.0193(5)
  C22	0.2491(2)	0.98238(16)	0.56983(12)	1	0.0210(5)
  C23	0.2120(2)	0.89286(16)	0.58578(12)	1	0.0225(5)
  H23A	0.1406	0.8932	0.618	1	0.027
  H23B	0.1873	0.8659	0.5406	1	0.027
  C24	0.3118(2)	0.84293(17)	0.61968(12)	1	0.0228(5)
  C25	0.3602(3)	0.7333(2)	0.69781(18)	1	0.0448(8)
  H25A	0.4231	0.7681	0.7195	1	0.067
  H25B	0.3973	0.6974	0.6618	1	0.067
  H25C	0.3218	0.6994	0.7348	1	0.067
  C31	0.1446(2)	1.02575(17)	0.53105(13)	1	0.0239(5)
  H31A	0.1214	0.9918	0.4892	1	0.029
  H31B	0.0735	1.0275	0.5635	1	0.029
  C32	0.1704(2)	1.11351(17)	0.50526(13)	1	0.0272(6)
  H32A	0.1946	1.1483	0.5463	1	0.033
  H32B	0.2387	1.1127	0.4708	1	0.033
  C33	0.0585(3)	1.1503(2)	0.46982(16)	1	0.0367(7)
  H33A	−0.0106	1.1443	0.5033	1	0.044
  H33B	0.0395	1.1164	0.4272	1	0.044
  C34	0.0638(3)	1.2404(2)	0.44632(14)	1	0.0348(7)
  C35	−0.0534(3)	1.2636(3)	0.4090(2)	1	0.0667(12)
  H35A	−0.0642	1.2289	0.3667	1	0.1
  H35B	−0.0499	1.3217	0.3946	1	0.1
  H35C	−0.122	1.2554	0.4417	1	0.1
  C36	0.0885(3)	1.2991(2)	0.50777(16)	1	0.0518(9)
  H36A	0.0919	1.3558	0.4897	1	0.078
  H36B	0.1664	1.2849	0.5301	1	0.078
  H36C	0.0232	1.2944	0.5432	1	0.078
  O1	0.37336(17)	1.07063(11)	0.35827(9)	1	0.0295(4)
  O2	0.2228(2)	0.58991(14)	0.51681(12)	1	0.0481(6)
  O3	0.4284(2)	0.60914(13)	0.53788(11)	1	0.0427(5)
  O4	0.34267(14)	0.94422(11)	0.46170(8)	1	0.0201(4)
  O5	0.45495(15)	1.02085(12)	0.53858(9)	1	0.0266(4)
  O6	0.27352(16)	1.02392(12)	0.63524(9)	1	0.0251(4)
  HO6	0.342(3)	1.033(2)	0.6369(17)	1	0.05
  O7	0.41851(16)	0.85198(13)	0.60753(11)	1	0.0356(5)
  O8	0.26888(16)	0.78534(13)	0.66423(11)	1	0.0366(5)
  O9	0.1644(2)	1.24749(16)	0.39741(12)	1	0.0513(6)
  HO9	0.160(3)	1.307(2)	0.3826(17)	1	0.05
  C51	0.1037(3)	0.4553(2)	0.31090(15)	1	0.0388(7)
  C52	0.1159(3)	0.5480(2)	0.3010(2)	1	0.0512(9)
  H52A	0.0462	0.5679	0.2723	1	0.061
  H52B	0.1112	0.5749	0.3484	1	0.061
  C53	0.2325(3)	0.57416(19)	0.26485(16)	1	0.0403(8)
  C54	0.3464(3)	0.57891(18)	0.30905(13)	1	0.0285(6)
  C55	0.2404(5)	0.5906(2)	0.19500(19)	1	0.0747(14)
  H55A	0.3166	0.6049	0.1745	1	0.09
  H55B	0.1697	0.5881	0.1659	1	0.09
  O51	0.00971(18)	0.41958(16)	0.29455(13)	1	0.0529(6)
  O52	0.19701(19)	0.41745(13)	0.33812(11)	1	0.0377(5)
  HO52	0.262(3)	0.454(2)	0.3511(17)	1	0.05
  O53	0.41850(17)	0.63675(12)	0.30044(10)	1	0.0344(5)
  O54	0.36137(17)	0.52002(13)	0.35372(10)	1	0.0346(5)

Example 11: Preparation and Analyses of Homoharringtonine Hydrogen Fumarate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial fumaric acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 103.5-107.2° C. (measured by DSC, see FIG. 3.10).
• DSC Analysis (See FIG. 3.10)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.80 (s, 1H), 6.74 (s, 1H), 6.65 (s, 2H), 6.09 (d, J=9.6 Hz, 1H), 5.96 (d, J=0.9 Hz, 1H), 5.93 (d, J=0.9 Hz, 1H), 5.33 (s, 1H), 4.17 (d, J=9.6 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 3H), 3.43-3.32 (m, 2H), 3.24-3.10 (m, 1H), 2.75-2.61 (m, 1H), 2.30-2.08 (m, 4H), 1.95 (d, J=16.1 Hz, 2H), 1.47-1.30 (m, 5H), 1.16 (s, 6H). *Partial presuppression of water signal using ‘watergate” irradiation
• ¹³C NMR (101 MHz, MeOD)** δ 135.91, 114.59, 111.56, 102.57, 95.74, 74.03, 58.74, 53.89, 52.92, 51.79, 49.56, 48.62, 44.47, 43.77, 40.59, 40.16, 28.94, 28.90, 28.88, 19.64, 18.81. **DEPT135: Distortionless Enhancement by Polarization Transfer (non-quaternary carbons only)
• IR (ATR, solid), cm⁻¹ 3607.9, 3212.6, 2955.6, 1980.4, 1777.4, 1731.4, 1708.1, 1653.6, 1584.3, 1505.9, 1488.6, 1440.0, 1372.4, 1338.6, 1292.0, 1251.1, 1221.1, 1173.3, 1150.9, 1119.3, 1088.7, 1034.0, 982.0, 934.1, 903.3, 839.6, 790.3, 761.8, 646.0, 613.5, 563.6, 510.2. See FIG. 1.10
• X-Ray Powder Diffraction
• The powder sample is well crystallised, with a peak width of 0.119° (2θ) at 19.564° (2θ) (for view of diagrams and experimental details, see FIG. 2.7.1).
Example 12: Preparation and Analyses of Homoharringtonine Hydrogen Tartronate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial tartronic acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 163.1-167.6° C. (measured by DSC, see FIG. 3.11).
• DSC Analysis (See FIG. 3.11)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.80 (s, 1H), 6.75 (s, 1H), 6.09 (d, J=9.6 Hz, 1H), 5.96 (d, J=0.9 Hz, 1H), 5.94 (d, J=0.9 Hz, 1H), 5.34 (s, 1H), 4.18 (d, J=9.6 Hz, 1H), 3.82 (s, 3H), 3.54 (s, 3H), 2.69 (m, 1H), 2.22 (m, 4H), 2.04-1.91 (m, 2H), 1.47-1.29 (m, 5H), 1.23 (m, 1H), 1.15 (s, 6H). *Partial presuppression of water signal using ‘watergate” irradiation
• ¹³C NMR (101 MHz, MeOD)** δ 114.60, 111.55, 102.61, 95.67, 74.02, 58.77, 53.94, 52.86, 51.79, 48.67, 44.47, 43.77, 40.59, 40.10, 28.94, 28.88, 28.84, 19.63, 18.80. **DEPT135: Distortionless Enhancement by Polarization Transfer (non-quaternary carbons only)
• IR (Diamond ATR, solid) cm ⁻¹ 3451, 2969, 2898, 2051, 1763, 1730, 1657, 1507, 1490, 1467, 1437, 1376, 1352, 1316, 1294, 1266, 1228, 1208, 1186, 1148, 1126, 1083, 1032, 1002, 985, 943, 927, 891, 866, 802, 753, 720, 690, 675, 652, 614, 563, 510, 477. See FIG. 1.11
• IR (Diamond ATR, film) cm ⁻¹ 3429, 2965, 1744, 1655, 1505, 1489, 1440, 1374, 1266, 1224, 1165, 1084, 1033, 928, 807, 615. See FIG. 1.11
Example 13: Preparation and Analyses of Homoharringtonine Hydrogen Malonate
• 
• This ionic compound was obtained from commercial homoharringtone mixed with commercial (2R)-citramalic acid according to the general procedure in which the solvent was methanol-d₄, then isolated as a white prismatic solid mp 127.0-131.9° C. (measured by DSC, see FIG. 3.12).
• DSC Analysis (See FIG. 3.12)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.81 (s, 1H), 6.75 (s, 1H), 6.10 (d, J=9.6 Hz, 1H), 5.97 (d, J=1.1 Hz, 1H), 5.94 (d, J=1.0 Hz, 1H), 5.34 (s, 1H), 4.18 (d, J=9.6 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 3H), 3.24-3.17 (m, 1H), 2.74-2.64 (m, 1H), 2.30-2.09 (m, 4H), 1.95 (d, J=16.1 Hz, 2H), 1.48-1.30 (m, 5H), 1.16 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR APT* (101 MHz, Methanol-d4) δ 174.83, 174.22, 171.62, 165.26, 149.82, 148.81, 130.79, 126.75, 114.88, 111.83, 102.90, 95.90, 78.32, 76.09, 74.30, 71.27, 59.04, 54.21, 53.18, 52.07, 48.94, 44.75, 44.05, 40.87, 40.42, 29.22, 29.17, 29.14, 19.91, 19.09. See FIG. 1.12 *APT=Attached Proton Test
• IR (Diamond ATR, solid) cm⁻¹ 3453.1, 2967.5, 2933.2, 2899.3, 1765.0, 1735.2, 1654.6, 1505.9, 1489.1, 1463.7, 1439.1, 1374.9, 1349.7, 1292.0, 1266.2, 1226.5, 1207.5, 1148.4, 1083.3, 1060.6, 1032.3, 1002.1, 985.4, 944.1, 925.5, 891.0, 858.5, 830.6, 797.6, 756.7, 721.5, 710.8, 690.8, 615.1, 565.1, 510.8, 498.3, 489.9, 478.9, 472.8. See FIG. 1.12
Example 14: Preparation and Analyses of Homoharringtonine Dihydrogen Citrate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial citric acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 170.35-173.9° C. (measured by DSC, see FIG. 3.13). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.13)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 6.80 (s, 1H), 6.75 (s, 1H), 6.09 (d, J=9.6 Hz, 1H), 5.96 (s, 1H), 5.94 (s, 1H), 5.33 (s, 1H), 4.17 (d, J=9.7 Hz, 1H), 3.81 (s, 3H), 3.54 (s, 3H), 2.79 (d, J=15.4 Hz, 2H), 2.71 (d, J=15.4 Hz, 2+1H), 2.23 (d, J=16.2 Hz, 1H), 1.95 (d, J=16.1 Hz, 1H), 1.49-1.17 (m, 6H), 1.15 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation
• ¹³C NMR APT*(101 MHz, Methanol-d₄) δ 179.22, 174.90, 174.22, 171.61, 165.22, 149.83, 148.81, 130.80, 126.75, 114.89, 111.84, 102.89, 95.97, 78.30, 76.09, 74.33, 74.01, 71.29, 59.05, 54.23, 53.21, 52.07, 48.95, 44.76, 44.06, 40.88, 40.44, 29.22, 29.18, 29.16, 19.92, 19.10. *APT=Attached Proton Test
• IR (Diamond ATR, solid) cm ⁻¹ 2959, 1757, 1732, 1715, 1651, 1580, 1508, 1489, 1464, 1432, 1371, 1305, 1262, 1224, 1186, 1151, 1111, 1081, 1032, 985, 944, 922, 909, 864, 829, 806, 705, 690, 614, 581, 563, 510, 486. See FIG. 1.13
• IR (Diamond ATR, film) cm ⁻¹ 3442, 2967, 1738, 1654, 1585, 1505, 1489, 1440, 1373, 1264, 1223, 1115, 1083, 1033, 928. See FIG. 1.13
• X-Ray Crystallographic Studies
• Single Crystal X-Ray Diffraction (See FIGS. 2.11.1 and 2.11.2)
• From a suspension in its mother liquor, a suitable single crystal of size 0.58×0.36×0.28 mm was finally selected and implemented on the diffractometer.

• Structural data

  Empirical formula	C36H51NO17
  Extended formula	C29H40NO9, C6H7O7, CH4O
  Formula weight	769.78
  Temperature	150(2) K
  Wavelength	0.71073 Å
  Crystal system, space group	orthorhombic, P 21 21 21
  Unit cell dimensions	a = 9.9967(3) Å, α = 90°
  	b = 18.8971(5) Å, β = 90°
  	c = 19.2826(7) Å, γ = 90°
  Volume	3642.6(2) Å3
  Z, Calculated density	4, 1.404 (g · cm−1)
  Absorption coefficient	0.112 mm−1
  F(000)	1640
  Crystal size	0.58 × 0.36 × 0.28 mm
  Crystal color	colourless
  Theta range for data collection	2.94 to 27.48°
  h_min, h_max	−12, 12
  k_min, k_max	−20, 24
  l_min, l_max	−25, 13
  Reflections collected/unique	18037/4637 [aR(int) = 0.0424]
  Reflections [I > 2σ]	4165
  Completeness to theta_max	0.998
  Absorption correction type	multi-scan
  Max. and min. transmission	0.969, 0.858
  Refinement method	Full-matrix least-squares on F2
  Data/restraints/parameters	4637/0/513
  bGoodness-of-fit	1.032
  Final R indices [I > 2σ]	cR1 = 0.0367, dwR2 = 0.0851
  R indices (all data)	cR1 = 0.0427, dwR2 = 0.0884
  Largest diff. peak and hole	0.289 and −0.214 e · Å−3

  
  Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
  U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIG. 2.11.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	0.3491(2)	0.92951(11)	0.25699(11)	1	0.0149(4)
  H1	0.3259	0.9482	0.2129	1	0.018
  C2	0.3729(2)	0.96852(11)	0.31322(11)	1	0.0152(4)
  C3	0.4025(2)	0.92636(11)	0.37724(10)	1	0.0138(4)
  H3	0.4934	0.9384	0.3953	1	0.017
  C4	0.3993(2)	0.84827(11)	0.35162(11)	1	0.0119(4)
  H4	0.4942	0.8317	0.3535	1	0.014
  C5	0.3638(2)	0.85222(11)	0.27257(11)	1	0.0136(4)
  C6	0.4667(2)	0.81449(12)	0.22685(11)	1	0.0176(5)
  H6A	0.4901	0.7677	0.2464	1	0.021
  H6B	0.5492	0.8431	0.2224	1	0.021
  C7	0.3972(3)	0.80632(13)	0.15620(12)	1	0.0220(5)
  H7A	0.4181	0.8469	0.1256	1	0.026
  H7B	0.4258	0.7621	0.133	1	0.026
  C8	0.2475(3)	0.80407(12)	0.17319(11)	1	0.0212(5)
  H8A	0.2	0.8437	0.1504	1	0.025
  H8B	0.2075	0.7589	0.1575	1	0.025
  N9	0.2393(2)	0.81069(9)	0.25106(9)	1	0.0141(4)
  HN9	0.251(4)	0.7629(18)	0.2669(17)	1	0.05
  C10	0.1057(2)	0.83634(12)	0.27463(11)	1	0.0172(5)
  H10A	0.0365	0.8014	0.2612	1	0.021
  H10B	0.0848	0.8815	0.251	1	0.021
  C11	0.1006(2)	0.84755(11)	0.35335(11)	1	0.0144(4)
  H11A	0.1348	0.8955	0.364	1	0.017
  H11B	0.0062	0.8455	0.3686	1	0.017
  C12	0.1806(2)	0.79388(11)	0.39455(11)	1	0.0130(4)
  C13	0.3209(2)	0.79563(10)	0.39455(11)	1	0.0118(4)
  C14	0.3947(2)	0.74640(11)	0.43291(11)	1	0.0141(4)
  H14	0.4897	0.7472	0.433	1	0.017
  C15	0.3252(2)	0.69701(11)	0.47031(11)	1	0.0153(4)
  C16	0.1875(2)	0.69386(11)	0.46951(11)	1	0.0153(4)
  C17	0.1124(2)	0.74148(11)	0.43253(11)	1	0.0159(4)
  H17	0.0174	0.7392	0.4325	1	0.019
  C18	0.2626(2)	0.59964(11)	0.52687(12)	1	0.0212(5)
  H18A	0.2671	0.5574	0.4966	1	0.025
  H18B	0.2624	0.5837	0.5758	1	0.025
  C19	0.3571(3)	1.07978(12)	0.25888(13)	1	0.0270(6)
  H19A	0.2638	1.0737	0.2445	1	0.041
  H19B	0.4165	1.0631	0.2219	1	0.041
  H19C	0.3746	1.13	0.2679	1	0.041
  C21	0.3353(2)	0.98104(10)	0.48356(11)	1	0.0126(4)
  C22	0.2160(2)	0.99292(11)	0.53183(11)	1	0.0140(4)
  C23	0.1479(2)	0.92348(11)	0.55222(11)	1	0.0162(4)
  H23A	0.0747	0.9336	0.5854	1	0.019
  H23B	0.1079	0.9015	0.5105	1	0.019
  C24	0.2446(2)	0.87236(11)	0.58470(11)	1	0.0160(4)
  C25	0.2645(3)	0.77137(12)	0.65633(13)	1	0.0259(5)
  H25A	0.3417	0.7932	0.6792	1	0.039
  H25B	0.2957	0.7397	0.6195	1	0.039
  H25C	0.2129	0.7442	0.6904	1	0.039
  C31	0.1157(2)	1.04230(11)	0.49544(12)	1	0.0172(5)
  H31A	0.0748	1.0168	0.4559	1	0.021
  H31B	0.0433	1.0545	0.5284	1	0.021
  C32	0.1792(2)	1.11061(11)	0.46873(12)	1	0.0195(5)
  H32A	0.2259	1.1006	0.4245	1	0.023
  H32B	0.247	1.1269	0.5026	1	0.023
  C33	0.0774(2)	1.16973(11)	0.45699(13)	1	0.0185(5)
  33A	0.0362	1.1819	0.5021	1	0.022
  H33B	0.0055	1.1515	0.4265	1	0.022
  C34	0.1343(2)	1.23774(11)	0.42451(12)	1	0.0177(5)
  C35	0.1490(3)	1.23004(14)	0.34612(13)	1	0.0286(6)
  H35A	0.1813	1.2747	0.3264	1	0.043
  H35B	0.062	1.2182	0.3257	1	0.043
  H35C	0.2132	1.1923	0.3358	1	0.043
  C36	0.2649(3)	1.26062(13)	0.45770(15)	1	0.0279(6)
  H36A	0.2555	1.26	0.5083	1	0.042
  H36B	0.2874	1.3086	0.4423	1	0.042
  H36C	0.3363	1.228	0.4439	1	0.042
  O1	0.38145(18)	1.03942(8)	0.32111(8)	1	0.0215(4)
  O2	0.14401(17)	0.63966(8)	0.51222(8)	1	0.0216(4)
  O3	0.37524(16)	0.64530(8)	0.51409(8)	1	0.0188(3)
  O4	0.30170(15)	0.93996(7)	0.42992(8)	1	0.0145(3)
  O5	0.44249(16)	1.00917(8)	0.49151(8)	1	0.0177(3)
  O6	0.26234(18)	1.02640(8)	0.59345(8)	1	0.0185(3)
  HO6	0.345(4)	1.0383(18)	0.5906(18)	1	0.05
  O7	0.36240(17)	0.87121(9)	0.57473(9)	1	0.0269(4)
  O8	0.18077(17)	0.82599(8)	0.62673(8)	1	0.0204(4)
  O9	0.03435(17)	1.29295(8)	0.43436(9)	1	0.0194(4)
  HO9	0.039(4)	1.3068(17)	0.4747(18)	1	0.047
  C51	0.2081(2)	0.62031(12)	0.26814(12)	1	0.0197(5)
  C52	0.2431(2)	0.55356(11)	0.31079(11)	1	0.0165(4)
  C53	0.1183(2)	0.53099(11)	0.35211(12)	1	0.0196(5)
  H53A	0.1	0.5667	0.3885	1	0.023
  H53B	0.0402	0.5298	0.3205	1	0.023
  C54	0.1343(2)	0.45913(12)	0.38583(12)	1	0.0215(5)
  O51	0.2755(2)	0.67426(8)	0.28230(9)	1	0.0293(4)
  O52	0.11948(19)	0.61575(9)	0.22240(10)	1	0.0300(4)
  O53	0.34983(17)	0.57012(9)	0.35660(9)	1	0.0221(4)
  HO53	0.358(4)	0.6160(18)	0.3535(18)	1	0.05
  O54	0.2279(2)	0.44156(10)	0.42120(12)	1	0.0433(6)
  O55	0.03274(18)	0.41626(9)	0.37134(8)	1	0.0204(4)
  HO55	0.044(4)	0.3790(18)	0.3902(18)	1	0.05
  C60	0.2959(2)	0.49411(12)	0.26327(12)	1	0.0204(5)
  H60A	0.3642	0.5153	0.2324	1	0.025
  H60B	0.3427	0.4594	0.2931	1	0.025
  C61	0.1992(3)	0.45307(13)	0.21778(13)	1	0.0251(5)
  O62	0.0989(2)	0.48721(10)	0.18875(10)	1	0.0344(5)
  H062	0.104(3)	0.5364(18)	0.2012(18)	1	0.05
  O63	0.2167(2)	0.39075(9)	0.20666(11)	1	0.0381(5)
  O71	0.5434(2)	1.13984(10)	0.43673(10)	1	0.0321(4)
  HO71	0.498(4)	1.1011(18)	0.4527(18)	1	0.05
  C72	0.6645(3)	1.11097(17)	0.41010(17)	1	0.0443(8)
  H72A	0.6436	1.0742	0.376	1	0.066
  H72B	0.7165	1.0903	0.4481	1	0.066
  H72C	0.7167	1.1485	0.3879	1	0.066

• X-Ray Powder Diffraction
• The powder sample is well crystallised, with a peak width of 0.127° (2θ) at 18.255° (2θ). The powder is constituted in major part by the expected sample referenced HOCIT 5776. However, the powder pattern reveals the presence of a second phase, with significant lines at 7.001° (2θ) and 12.317° (2θ) for example, not calculated from the structure determined with a single crystal (for view of diagrams and experimental details, see FIG. 2.11.3).
Example 15: Preparation and Analyses of Homoharringtonine Salicylate
• 
• This ionic compound was obtained from commercial homoharringtonine mixed with commercial salicylic acid according to the general procedure in which the solvent was methanol, then isolated as a white prismatic solid mp 148.7-151.3° C. (measured by DSC, see FIG. 3.14). Several potentially acceptable crystals were kept suspended in their mother liquors for the subsequent X-ray diffraction analysis. (see below).
• DSC Analysis (See FIG. 3.14)
• ¹H NMR (400 MHz, Methanol-d₄)*δ 7.80 (dd, J=7.7, 1.7 Hz, 1H), 7.26 (ddd, J=8.8, 7.2, 1.8 Hz, 1H), 6.80-6.70 (m, 4H), 6.09 (d, J=9.6 Hz, 1H), 5.92 (d, J=1.0 Hz, 1H), 5.88 (d, J=1.0 Hz, 1H), 5.33 (s, 1H), 4.17 (d, J=9.6 Hz, 1H), 3.81 (s, 3H), 3.54 (s, 3H), 3.18 (dd, J=11.0, 6.9 Hz, 1H), 2.71-2.62 (m, 1H), 2.28-2.08 (m, 4H), 1.95 (d, J=16.1 Hz, 1H), 1.47-1.30 (m, 5H), 1.30-1.18 (m, 1H), 1.16 (s, 6H). *Partial presuppression of water signal using ‘watergate’ irradiation.
• ¹³C NMR (101 MHz, MeOD)** δ 133.50, 131.36, 118.66, 116.85, 114.49, 111.46, 102.48, 95.80, 74.04, 58.71, 53.86, 52.96, 51.78, 49.56, 48.62, 44.45, 43.75, 40.58, 40.24, 28.96, 28.94, 28.86, 19.65, 18.79. **DEPT135: Distortionless Enhancement by Polarization Transfer (non-quaternary carbons only)
• IR (Diamond ATR, solid) cm⁻¹ 2961.4, 2622.5, 1760.5, 1748, 1740.7, 1722.8, 1651.8, 1625.2, 1590.4, 1579.2, 1503.9, 1487.7, 1459.3, 1374, 1334.4, 1293.2, 1224.3, 1167.4, 1082.6, 1043.9, 1030.5, 995.4, 924.5, 890.7, 857.3, 832.8, 805.3, 763.6, 704.8, 666.2, 613.2, 565.6. See FIG. 1.14
• IR (Diamond ATR, film) cm⁻¹ 3416.8, 2962.9, 2377.4, 2156.9, 1746.7, 1655.2, 1628.2, 1591.3, 1504.8, 1488.2, 1459.5, 1375.8, 1330.2, 1223.6, 1084.2, 1034.5, 930.1, 858.3, 807.3, 763.1, 705.4. See FIG. 1.14
• X-Ray Crystallographic Studies
• Single Crystal X-Ray Diffraction (See FIG. 2.12.1 to 2.12.4)
• From a suspension in its mother liquor, a small single crystal of size 0.15×0.11×0.04 mm was finally selected and implemented on the diffractometer.

• Structural data

  Empirical formula	C72H94N2O26
  Extended formula	2(C29H40NO9), 2(C7H5O3), 2(H2O)
  Formula weight	1403.5
  Temperature	150(2) K
  Wavelength	0.71073 Å
  Crystal system, space group	monoclinic, P 21
  Unit cell dimensions	a = 11.6871(3) Å, α = 90°
  	b = 25.8294(6) Å, β = 114.6320(10)°
  	c = 12.6300(3) Å, γ = 90°
  Volume	3465.69(15) Å3
  Z, Calculated density	2, 1.345 (g · cm−1)
  Absorption coefficient	0.102 mm−1
  F(000)	1496
  Crystal size	0.15 × 0.11 × 0.04 mm
  Crystal color	colourless
  Theta range for data collection	2.96 to 27.48°
  h_min, h_max	−15, 15
  k_min, k_max	−33, 33
  l_min, l_max	−11, 16
  Reflections collected/unique	29505/8078 [aR(int) = 0.0621]
  Reflections [I > 2σ]	6299
  Completeness to theta_max	0.994
  Absorption correction type	multi-scan
  Max. and min. transmission	0.996, 0.886
  Refinement method:	Full-matrix least-squares on F2
  Data/restraints/parameters	8078/1/928
  bGoodness-of-fit	1.076
  Final R indices [I > 2σ]	cR1 = 0.0619, dwR2 = 0.121
  R indices (all data)	cR1 = 0.086, dwR2 = 0.1312
  Largest diff. peak and hole	0.531 and −0.3 eÅ−3

• Atomic coordinates, site occupancy (%) and equivalent isotropic displacement parameters (A²×10³).
• U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
• Atom numbering of FIG. 2.12.1 corresponds to below table.

• Atom	x	y	z	occ.	U(eq)
  C1	−0.3818(4)	0.00999(17)	0.1577(4)	1	0.0196(9)
  H1	−0.3779	−0.0157	0.1054	1	0.024
  C2	−0.3310(4)	0.00487(17)	0.2729(4)	1	0.0193(9)
  C3	−0.3588(4)	0.04946(17)	0.3333(4)	1	0.0186(9)
  H3	−0.4173	0.038	0.3682	1	0.022
  C4	−0.4266(4)	0.08958(17)	0.2350(4)	1	0.0172(9)
  H4	−0.5126	0.0945	0.2325	1	0.021
  C5	−0.4453(4)	0.06061(18)	0.1208(4)	1	0.0183(9)
  C6	−0.5832(4)	0.0587(2)	0.0314(4)	1	0.0298(11
  H6A	−0.627	0.0292	0.0483	1	0.036
  H6B	−0.6271	0.091	0.0347	1	0.036
  C7	−0.5836(6)	0.0525(3)	−0.0867(5)	1	0.0523(19
  H7A	−0.6431	0.0772	−0.1428	1	0.063
  H7B	−0.6082	0.0169	−0.1162	1	0.063
  C8	−0.4507(5)	0.0637(2)	−0.0699(4)	1	0.0287(11
  H8A	−0.4066	0.0313	−0.0719	1	0.034
  H8B	−0.4502	0.0871	−0.1318	1	0.034
  N9	−0.3883(4)	0.08909(15)	0.0468(3)	1	0.0179(8)
  HN9	−0.406(6)	0.119(3)	0.038(6)	1	0.0
  C10	−0.2485(4)	0.08986(18)	0.0908(4)	1	0211(10
  H10A	−0.2248	0.1127	0.0402	1	0.025
  H10B	−0.2186	0.0545	0.0856	1	0.025
  C11	−0.1831(4)	0.10881(17)	0.2165(4)	1	0.0176(9)
  H11A	−0.1748	0.0794	0.2696	1	0.021
  H11B	−0.0973	0.1207	0.2312	1	0.021
  C12	−0.2525(4)	0.15248(17)	0.2444(4)	1	0.0165(9)
  C13	−0.3674(4)	0.14288(17)	0.2526(4)	1	0.0151(9)
  C14	−0.4317(4)	0.18343(17)	0.2773(4)	1	0.0167(9)
  H14	−0.5087	0.1775	0.2838	1	0.0
  C15	−0.3799(4)	0.23192(17)	0.2919(4)	1	0.0181(9)
  C16	−0.2683(4)	0.24154(17)	0.2810(4)	1	0.0179(9)
  C17	−0.2022(4)	0.20246(17)	0.2595(4)	1	0.0175(9)
  H17	−0.1243	0.209	0.2551	1	0.021
  C18	−0.3495(5)	0.3174(2)	0.2989(6)	1	0.0342(13
  H18A	−0.3276	0.3447	0.3591	1	0.041
  H18B	−0.3985	0.3333	0.2218	1	0.041
  C19	−0.2286(5)	−0.07362(19)	0.2749(5)	1	0.0287(11
  H19A	−0.3051	−0.09	0.218	1	0.043
  H19B	−0.1753	−0.0999	0.329	1	0.043
  H19C	−0.1826	−0.0574	0.2342	1	0.043
  C21	−0.2376(4)	0.07232(16)	0.5324(4)	1	0.0150(9)
  C22	−0.1193(4)	0.10173(17)	0.6134(4)	1	0.0181(9)
  C23	−0.1290(4)	0.15962(16)	0.5815(4)	1	0.0210(10
  H23A	−0.0436	0.1748	0.6184	1	0.025
  H23B	−0.1574	0.1625	0.4961	1	0.025
  C24	−0.2154(4)	0.19169(17)	0.6156(4)	1	0.0191(9)
  C25	−0.4265(5)	0.2160(2)	0.5670(5)	1	0.0293(12
  H25A	−0.4225	0.2098	0.645	1	0.044
  H25B	−0.5115	0.2084	0.5085	1	0.044
  H25C	−0.4059	0.2523	0.5602	1	0.044
  C31	−0.0033(4)	0.07965(17)	0.6007(4)	1	0.0186(9)
  H31A	−0.0119	0.0866	0.5206	1	0.022
  H31B	0.0725	0.0983	0.6551	1	0.022
  C32	0.0168(4)	0.02207(17)	0.6244(4)	1	0.0219(10
  H32A	−0.059	0.003	0.5716	1	0.026
  H32B	0.0297	0.0148	0.7056	1	0.026
  C33	0.1312(4)	0.00353(17)	0.6058(4)	1	0.0203(10
  H33A	0.2055	0.0237	0.6578	1	0.024
  H33B	0.117	0.0115	0.5246	1	0.024
  C34	0.1622(4)	−0.05425(18)	0.6277(4)	1	0.0224(10)
  C35	0.0526(5)	−0.0876(2)	0.5504(5)	1	0.0333(12)
  H35A	0.0218	−0.0755	0.4698	1	0.05
  H35B	−0.0153	−0.0853	0.5766	1	0.05
  H35C	0.0803	−0.1237	0.555	1	0.05
  C36	0.2022(6)	−0.0690(2)	0.7544(5)	1	0.0418(14)
  H36A	0.2289	−0.1053	0.7657	1	0.063
  H36B	0.1312	−0.0643	0.7756	1	0.063
  H36C	0.2724	−0.0469	0.8038	1	0.063
  O1	−0.2627(3)	−0.03428(12)	0.3396(3)	1	0.0245(7)
  O2	−0.4215(3)	0.27736(13)	0.3215(3)	1	0.0295(8)
  O3	−0.2371(3)	0.29334(12)	0.3015(3)	1	0.0291(8)
  O4	−0.2456(3)	0.07096(12)	0.4237(3)	1	0.0193(7)
  O5	−0.3115(3)	0.05224(13)	0.5638(3)	1	0.0272(8)
  O6	−0.1014(3)	0.09442(13)	0.7304(3)	1	0.0232(7)
  HO6	−0.159(6)	0.100(3)	0.736(6)	1	0.05
  O7	−0.1806(3)	0.22291(14)	0.6937(3)	1	0.0343(9)
  O8	−0.3364(3)	0.18247(12)	0.5481(3)	1	0.0231(7)
  O9	0.2605(3)	−0.06667(14)	0.5922(4)	1	0.0349(9)
  HO9	0.319(6)	−0.049(3)	0.633(6)	1	0.05
  C41	−0.4061(4)	0.20979(18)	−0.0709(4)	1	0.0185(9)
  C42	−0.4133(4)	0.26758(17)	−0.0845(4)	1	0.0190(9)
  C43	−0.4734(4)	0.29825(18)	−0.0317(4)	1	0.0236(10)
  C44	−0.4734(5)	0.3520(2)	−0.0387(5)	1	0.0348(13)
  H44	−0.5137	0.3723	−0.0014	1	0.042
  C45	−0.4139(5)	0.3755(2)	−0.1008(5)	1	0.0361(13)
  H45	−0.4138	0.4122	−0.106	1	0.043
  C46	−0.3542(5)	0.3463(2)	−0.1557(5)	1	0.0320(12)
  H46	−0.3132	0.3627	−0.1977	1	0.038
  C47	−0.3558(4)	0.2929(2)	−0.1480(4)	1	0.0252(11)
  H47	−0.3169	0.2728	−0.1868	1	0.03
  O41	−0.3392(3)	0.18505(13)	−0.1087(3)	1	0.0267(8)
  O42	−0.4676(3)	0.18943(12)	−0.0187(3)	1	0.0218(7)
  O43	−0.5327(4)	0.27633(14)	0.0297(4)	1	0.0331(9)
  HO43	−0.525(6)	0.249(3)	0.031(6)	1	0.05
  C51	0.0847(4)	0.26596(17)	−0.0909(4)	1	0.0198(10)
  H51	0.0267	0.2505	−0.161	1	0.024
  C52	0.1215(4)	0.31517(18)	−0.0810(4)	1	0.0200(10)
  C53	0.2190(4)	0.32915(16)	0.0374(4)	1	0.0164(9)
  H53	0.3014	0.3357	0.0333	1	0.02
  C54	0.2289(4)	0.27955(16)	0.1123(4)	1	0.0136(9)
  H54	0.3181	0.2674	0.1417	1	0.016
  C55	0.1468(4)	0.23828(16)	0.0226(4)	1	0.0142(8)
  C56	0.2210(4)	0.18952(17)	0.0199(4)	1	0.0199(9)
  H56A	0.2763	0.1964	−0.0202	1	0.024
  H56B	0.2728	0.1769	0.0997	1	0.024
  C57	0.1175(4)	0.15039(18)	−0.0484(4)	1	0.0243(10)
  H57A	0.0894	0.1551	−0.1334	1	0.029
  H57B	0.148	0.1144	−0.0276	1	0.029
  C58	0.0111(4)	0.16215(17)	−0.0123(4)	1	0.0216(10)
  H58A	0.0026	0.134	0.0371	1	0.026
  H58B	−0.0697	0.166	−0.0817	1	0.026
  N59	0.0475(3)	0.21301(14)	0.0560(3)	1	0.0161(8)
  HN59	0.088(5)	0.199(2)	0.139(5)	1	0.05
  C60	−0.0649(4)	0.24526(18)	0.0388(4)	1	0.0199(10)
  H60A	−0.1166	0.2267	0.0718	1	0.024
  H60B	−0.1165	0.2495	−0.0458	1	0.024
  C61	−0.0319(4)	0.29898(18)	0.0951(4)	1	0.0188(9)
  H61A	−0.0155	0.3225	0.0412	1	0.023
  H61B	−0.1057	0.3126	0.1056	1	0.023
  C62	0.0809(4)	0.29972(16)	0.2115(4)	1	0.0143(9)
  C63	0.2020(4)	0.28854(16)	0.2193(4)	1	0.0135(8)
  C64	0.3049(4)	0.28691(17)	0.3276(4)	1	0.0156(9)
  H64	0.3865	0.2784	0.3338	1	0.019
  C65	0.2853(4)	0.29777(17)	0.4240(4)	1	0.0179(9)
  C66	0.1677(4)	0.31120(17)	0.4167(4)	1	0.0197(10)
  C67	0.0638(4)	0.31097(16)	0.3130(4)	1	0.0188(9)
  H67	−0.0174	0.3182	0.3094	1	0.023
  C68	0.3079(5)	0.3226(2)	0.6008(4)	1	0.0320(12)
  H68A	0.3372	0.3589	0.6181	1	0.038
  H68B	0.3258	0.3046	0.6753	1	0.038
  C69	−0.0155(6)	0.3400(2)	−0.2692(5)	1	0.0428(15)
  H69A	0.014	0.314	−0.3086	1	0.064
  H69B	−0.0446	0.3707	−0.3186	1	0.064
  H69C	−0.0852	0.3256	−0.2545	1	0.064
  C71	0.2427(4)	0.41910(16)	0.0877(4)	1	0.0159(9)
  C72	0.2104(5)	0.45689(17)	0.1661(5)	1	0.0244(11)
  C73	0.2446(5)	0.4339(2)	0.2868(4)	1	0.0288(11)
  H73A	0.2371	0.4613	0.3385	1	0.035
  H73B	0.1834	0.4063	0.2808	1	0.035
  C74	0.3766(5)	0.4115(2)	0.3417(4)	1	0.0286(11)
  C75	0.5447(5)	0.3850(3)	0.5159(5)	1	0.0448(15)
  H75A	0.5447	0.3514	0.4801	1	0.067
  H75B	0.5651	0.3802	0.5988	1	0.067
  H75C	0.6078	0.4076	0.5075	1	0.067
  C81	0.0688(5)	0.46846(19)	0.1066(5)	1	0.0297(12)
  H81A	0.0225	0.4358	0.1018	1	0.036
  H81B	0.0477	0.4926	0.1566	1	0.036
  C82	0.0219(5)	0.4915(2)	−0.0146(5)	1	0.0379(14)
  H82A	0.0717	0.477	−0.0546	1	0.045
  H82B	0.0364	0.5294	−0.0077	1	0.045
  C83	−0.1172(5)	0.4814(2)	−0.0889(5)	1	0.0378(13)
  H83A	−0.1271	0.4443	−0.111	1	0.045
  H83B	−0.1636	0.4874	−0.0399	1	0.045
  C84	−0.1788(5)	0.5126(2)	−0.1973(5)	1	0.0353(13)
  C85	−0.3125(6)	0.4957(3)	−0.2704(6)	1	0.0532(17)
  H85A	−0.3601	0.4953	−0.2222	1	0.08
  H85B	−0.3123	0.4609	−0.3012	1	0.08
  H85C	−0.352	0.52	−0.3352	1	0.08
  C86	−0.1053(6)	0.5173(3)	−0.2700(5)	1	0.0439(15)
  H86A	−0.1535	0.5378	−0.3398	1	0.066
  H86B	−0.0895	0.4828	−0.2931	1	0.066
  H86C	−0.0248	0.5345	−0.2246	1	0.066
  O51	0.0848(3)	0.35381(13)	−0.1615(3)	1	0.0285(8)
  O52	0.3708(3)	0.29717(14)	0.5395(3)	1	0.0264(8)
  O53	0.1754(3)	0.32134(13)	0.5276(3)	1	0.0260(7)
  O54	0.1836(3)	0.37380(11)	0.0855(3)	1	0.0184(7)
  O55	0.3039(3)	0.42839(12)	0.0351(3)	1	0.0225(7)
  O56	0.2839(4)	0.50176(14)	0.1739(4)	1	0.0364(9)
  HO56	0.272(6)	0.531(3)	0.200(6)	1	0.05
  O57	0.4356(3)	0.39631(15)	0.2885(3)	1	0.0382(9)
  O58	0.4187(4)	0.40908(16)	0.4575(3)	1	0.0409(10)
  O59	−0.1879(4)	0.56408(15)	−0.1531(4)	1	0.0467(10)
  H59	−0.2274	0.5839	−0.2093	1	0.07
  C91	0.2069(5)	0.15694(19)	0.3512(5)	1	0.0274(11)
  C92	0.2274(4)	0.16464(17)	0.4767(4)	1	0.0223(10)
  C93	0.1463(3)	0.19621(14)	0.5016(3)	1	0.0268(11)
  H93	0.0736	0.2099	0.4399	1	0.032
  C94	0.1706(3)	0.20812(14)	0.6171(3)	1	0.0321(12)
  H94	0.1166	0.2309	0.6341	1	0.039
  C95	0.2751(5)	0.1862(2)	0.7069(5)	1	0.0376(13)
  H95	0.2916	0.1937	0.7856	1	0.045
  C96	0.3549(5)	0.1536(2)	0.6824(5)	1	0.0340(13)
  H96	0.4255	0.1386	0.7441	1	0.041
  C97	0.3320(5)	0.1430(2)	0.5688(5)	1	0.0286(11)
  O91	0.1084(3)	0.17337(13)	0.2713(3)	1	0.0265(8)
  O92	0.2952(4)	0.13363(15)	0.3347(3)	1	0.0370(9)
  O93	0.4150(3)	0.11174(15)	0.5479(4)	1	0.0363(9)
  HO93	0.369(6)	0.114(3)	0.462(6)	1	0.05
  OW1	0.4458(4)	0.01162(15)	0.6698(4)	1	0.0458(10)
  OW2	0.6810(3)	0.11024(14)	0.7538(3)	1	0.0318(8)

Example 16: Purification of Natural Homoharringtonine as Hydrogen (2R,3R)-Tartaric Salt
• All operations were performed in a sterile isolator using dedicated or single-use equipment. The reagents were of pharmacopoeial quality and all the quality control and quality assurance written procedures were carried out according to the current good manufacturing practices. Commercial homoharringtonine base (100 grams) exhibiting at least 97% of purity was dried then introduced in a dedicated sterile flask equipped with a stirring and a refrigerant, and flushed by sterile argon, then 1.2 molar equivalent of (2R,3R)-(+)-tartaric acid (natural version, pharmacopoeia quality) was introduced. Then 350 mL of anhydrous methanol was added under reflux until all solid phase disappeared. A volume of dry methanol was added to move away from the point of supersaturation. The homogeneous solution was then withdrawn and directly filtered hot under vacuum on a microporous filter (0.5 micron). After 15 minutes, fine translucent prismatic crystals of homohamrngtonine hydrogen (2R, 3R) tartrate begin to form. The stirred suspension is allowed to stand for 12 hours. At this stage an in process control (CIP) to check the impurity content of the crystals and mother liquors. The suspension is drained on a filter funnel (Buchner) and the crystals are dissolved in hot methanol. The crystallization operation and the corresponding CIPs are renewed twice. After the last wringing, the crystals were dried under vacuum at a temperature of 45c, 20 hours, and then packaged. Final samples are taken to carry out an analysis report in accordance with the specifications. The impurity content is less than 0.3% and the purity (HPC) exceeds 99.7% (the current purity of semi-synthetic batches). In addition to the usual tests including microbiological testing and endotoxin detection, all batches of drug substance were subjected to a high resolution NMR analysis and a control for in vivo toxicity.

Claims (31)

1. A harringtonines salt in the crystalline state exhibiting a protonated nitrogen seen in solid state analysis and having formula 1,

comprising solvate, made by reacting a cephalotaxine ester having formula 2,

in which R¹ is, but not limited to, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, and R² is, independently, but not limited to H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, with an acid having general formula AH in a crystallization solvent, wherein the said salt has a water or alkohol solubility ranged approximately from 5 mg/mL to approximately 100 mg/Ml.

2. The salt of claim 1 wherein the cephalotaxine ester reactant is homoharringtonine (=omacetaxine) having formula 2 in which R² is hydrogen and R1 have below formula 3.

3. The salts of claim 1 wherein the acid is an organic acid but not limited to, selected among the following list: fumaric, maleic, citramalic, malic, tartaric, tartronic, succinic, itaconic, citric acid or salicylic acid.

4. The salts of claim 1, having below formula

in which the malic acid is of configuration 2S having formula

5. The salts of claim 4, wherein the malic acid is of configuration 2R having formula

6. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine hydrogen (R)-malate exhibiting the below formula:

7. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtone hydrogen succinate exhibiting the below formula:

8. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine hydrogen (2′″S,3′″S)-tartrate exhibiting the below formula:

9. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine hydrogen (2′″R,3′″R)-tartrate exhibiting the below formula:

10. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine hydrogen itaconate exhibiting the below formula:

11. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine hydrogen fumarate exhibiting the below formula:

12. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine hydrogen tartronate exhibiting the below formula:

13. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine hydrogen malonate exhibiting the below formula:

14. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine dihydrogen citrate exhibiting the below formula:

15. The salt of claim 1, named (3S,4S,5R,2′R)-homoharringtonine salicate exhibiting the below formula:

16. The salt of claim 1 as crystalline form comprising solvate and co-crystal.

17. The cation (3S,4S,5R,2′R)-homoharringtoninium as described in FIGS. 2.3.1, 2.4.1, 2.5.1, 2.6.1, 2.8.1, 2.9.1, 2.11.1, and 2.12.1, exhibiting the below formula

18. The process of preparation and purification of salts of claim 1 comprising contacting a natural, hemi-synthetic or synthetic harringtonine or its semi-synthetic analog with a weak acid in suspension or in solution in a suitable non-aqueous solvent, preferably an alcohol or mixed at the solid state either at the amorphous state or at the crystalline state then recrystallized said salt in a suitable non aqueous solvent, preferably an alcohol, the said process being also when repeated a method of purification including enantiomeric (fractional crystallization).

19. The process of claim 18 wherein the harringtonine is homoharringtonine having formula represented in claim 2.

20. The process of claim 18 wherein the harringtonine is an harringtonine analog having general formula:

in which R¹ is, but not limited to, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl, and R² is, independently, but not limited to H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl.

21. The process of claim 18, wherein the acid is, but not limited to, selected among the following list: fumaric, maleic, citramalic, malic, tartaric, tartronic, succinic, itaconic, salicylic or citric acid.

22. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a mineral or organic salt or solvate or co-crystal of claim 1.

23. A method of treatment comprising administering a therapeutically effective amount of a pharmaceutical dosage form of claim 22 to a patient or an animal suffering from cancer including their metastasis, leukemia, lymphoma, parasitic disease, ocular proliferation and/or immune disorder and/or from viral disease.

24. A method of treating cancer, leukemia and/or lymphoma, comprising administering to a patient or an animal in need thereof the pharmaceutical dosage of claim 22, said pharmaceutical dosage being administered alone or in combination with at least another chemotherapeutic agents, eventually combined with radiotherapy.

25. The method of claim 24, wherein the leukemia is acute myelod leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative disorders including chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelosclerosis, and

wherein the lymphoma is a multiple myeloma, a Hodgkin disease or a Burkitt lymphoma, and

wherein the cancer is a breast cancer, a brain cancer or a lung cancer.

26. The method of claim 25, wherein the breast cancer is a triple negative breast cancer (TNBC).

27. The method of claim 25 wherein the brain cancer is a neuroblastoma.

28. The method of claim 25, wherein the lung cancer is a non small cell lung cancer (NSCLC).

29. A method for treating autoimmune disorder, comprising administering to a patient or an animal in need thereof the pharmaceutical dosage of claim 22, said pharmaceutical dosage being administered alone or in combination with at least another chemotherapeutic agent.

30. The method of claim 29, wherein the autoimmune disorder is a systemic lupus erythematosus (SLE), a dermatomyositis, a psoriasis or a lichen planopilaris (LPP).

31. The method of claim 30, wherein the lichen planopilaris (LPP) is a frontal fibrosis alopecia (FFA).

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