Synthesis Process of X-IPM, Stable Crystal Form and Application Thereof

Abstract

The present application relates to a new method for synthesizing isophosphoramide nitrogen mustard (X-IPM) that is suitable for industrialized production, involves fewer types of solvents, and leads to stable products with high yield. This method is charazterized mainly by the batchwise addition of M (e.g., M is R.sub.3N with R being ethyl; i.e., M is triethylamine) and the specific post-reaction treatment, which make it possible for the reaction to fully proceed, lead to products with less impurities, high yield and relatively stable properties, and can lead to stable crystallized substances with specific crystal structures. The present application also relates to stable crystal forms of the isophosphoramide nitrogen mustard (X-IPM) prepared by the aforementioned method, and use of the same as reactants for the synthesis of aziridine structure-containing compounds.

Claims

1. A process for producing X-IPM of formula III, comprising the following steps: ##STR00095## (1) mixing dichloromethane with 2-haloethylamine hydrohalide I, starting stirring and setting the temperature down to 70 C. to 60 C., and when the temperature is reduced to 30 C. to 20 C., adding phosphorus oxyhalide II; (2) adding dropwise a solution of compound M in dichloromethane in batches at a temperature range of 70 C. to 40 C.: {circle around (1)} for the first dropwise addition, the solution of compound M in dichloromethane comprises compound M in an amount 1.8 to 2.2 times the molar equivalent of phosphorus oxyhalide II, and the rate of the dropwise addition should ensures that the temperature change of the reaction system is within 10 C.; {circle around (2)} for the second dropwise addition, the solution of compound M in dichloromethane comprises compound M in an amount 0.9 to 1.1 times the molar equivalent of phosphorus oxyhalide II, and the rate of the dropwise addition should ensures that the temperature change of the reaction system is within 10 C.; and {circle around (3)} for the nth dropwise addition, the aforementioned dropwise addition step is repeated, the temperature of the system is increased by 5 C. to 15 C. with each addition, and the molar equivalent of compound M is decreased with each addition since the second dropwise addition; (3) after the completion of the reaction, carrying out post-treatment to obtain a product; wherein the n is an integer, and n2; X in the 2-haloethylamine hydrohalide I and X-IPM are identical, and both are Br or Cl; Z in the 2-haloethylamine hydrohalide I is Br or Cl; Y in the phosphorus oxyhalide II is Br or Cl; and the M is pyridine or R.sub.3N, wherein the three R groups are each independently methyl, ethyl, propyl or isopropyl.

2. The process according to claim 1, wherein R is ethyl (i.e., M is triethylamine), comprising the following steps: mixing dichloromethane with 2-haloethylamine hydrohalide I, starting stirring and setting the temperature down to 70 C. to 60 C., and when the temperature is reduced to 30 C. to 20 C., adding phosphorus oxyhalide II; adding triethylamine for the first time: when the temperature is lowered to a range of 70 C. to 60 C., adding dropwise a solution of triethylamine in dichloromethane, which comprises triethylamine in an amount 1.8 to 2.2 times the molar equivalent of phosphorus oxyhalide II, and the rate of the dropwise addition should ensures that the temperature of the reaction system is below 60 C.; adding triethylamine for the second time: when the temperature is raised to a range of 60 C. to 50 C., adding dropwise a solution of triethylamine in dichloromethane, which comprises triethylamine in an amount 0.9 to 1.1 times the molar equivalent of phosphorus oxyhalide II, and the rate of the dropwise addition should ensures that the temperature of the reaction system is below 50 C.; adding triethylamine for the third time: when the temperature is raised to a range of 50 C. to 40 C., adding dropwise a solution of triethylamine in dichloromethane, which comprises triethylamine in an amount 0.9 to 1.1 times the molar equivalent of phosphorus oxyhalide II, and the rate of the dropwise addition should ensures that the temperature of the reaction system is below 40 C.; after adding dropwise the solution of triethylamine in dichloromethane, raising the temperature to 20 C. to 10 C. for reaction until the reaction is completed, and carrying out post-treatment to obtain a product; wherein X in the 2-haloethylamine hydrohalide I and X-IPM are identical, and both are Br or Cl; Z in the 2-haloethylamine hydrohalide I is Br or Cl; and Y in the phosphorus oxyhalide II is Br or Cl.

3. The process according to claim 2, wherein when X in 2-haloethylamine hydrohalide I and X-IPM, Y in phosphorus oxyhalide II, and Z in 2-haloethylamine hydrohalide I are all Br, the post-treatment process for obtaining a product is as follows: starting to add water dropwise at 20 C. to 10 C. at a rate which should ensure that the temperature of the reaction system is below 10 C., after the dropwise addition, raising the temperature to 5 C. to 5 C., maintaining this temperature and continuing to stir for 8-12 hours, filtering the reaction solution, beating the obtained filter cake with water, dichloromethane, and acetone in sequence, and collecting and drying the filter cake to obtain Br-IPM as a solid; when X in 2-haloethylamine hydrohalide I and X-IPM, and Z in 2-haloethylamine hydrohalide I are all C.sub.1, and Y in phosphorus oxyhalide II is Br, the post-treatment process for obtaining a product is as follows: performing filtration, washing the filter residue with dichloromethane, combining the filtrate and washing liquid to obtain a combined reaction solution, heating the reaction solution to 0 C. to 5 C., then adding ice water at a rate which should ensure that the temperature of the reaction system is below 5 C., stirring for 2-6 h, filtering the reaction solution, beating the obtained filter cake with ice water and acetone in sequence, and collecting and drying the filter cake to obtain Cl-IPM as a solid.

4. The process according to claim 2, wherein dichloromethane and 2-haloethylamine hydrohalide I are mixed in a ratio of 1 ml of dichloromethane to 0.04 to 0.18 g of 2-haloethylamine hydrohalide I; the water contents of 2-haloethylamine hydrohalide I, dichloromethane and triethylamine used in the reaction process are controlled within 0.5% by mass.

5. The process according to claim 2, wherein when triethylamine is added for the first time, the solution of triethylamine in dichloromethane added dropwise comprises triethylamine and dichloromethane in a volume ratio of 0.40-1.20 ml of triethylamine to 1 ml of dichloromethane; when triethylamine is added for the second time, the solution of triethylamine in dichloromethane added dropwise comprises triethylamine and dichloromethane in a volume ratio of 0.20-0.60 ml of triethylamine to 1 ml of dichloromethane; and when triethylamine is added for the third time, the solution of triethylamine in dichloromethane added dropwise comprises triethylamine and dichloromethane in a volume ratio of 0.20-0.60 ml of triethylamine to 1 ml of dichloromethane.

6. The process according to claim 3, wherein the temperature for drying the solid Br-IPM or Cl-IPM does not exceed 35 C.

7. A crystal form of Br-IPM, characterized in that the crystal form of Br-IPM meets one of the following conditions: a melting point of 106 to 107 C. as determined by melting point measurements; an endothermic peak at 117.5-119.5 C. and an endothermic value of 1.65 to 1.85 mW/mg as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern represented by the diffraction angle 2 with characteristic peaks at 7.77, 15.57 and 19.01, with an error not greater than 0.01 as determined by X-ray powder diffraction using Cu-K radiation.

8. The crystal form of Br-IPM according to claim 7, characterized by an endothermic peak at 118.41 C. (with an error of 1 C.); and an endothermic value of 1.75 mW/mg as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern represented by the diffraction angle 2 with characteristic peaks at 7.77, 15.57, 19.01, 21.93, 22.71, 23.45, 23.84, 24.42, 25.05, 27.44, 27.99, 30.43, 31.42, 33.40, 33.75, 36.78, 39.55, 43.03 and 44.97, with an error not greater than 0.01 as determined by X-ray powder diffraction using Cu-K radiation.

9. The crystal form of Br-IPM according to claim 7, characterized in that the crystal form of Br-IPM meets one of the following conditions: it has the X-ray powder diffraction pattern as shown in FIG. 9; and it has the differential scanning calorimetry pattern as shown in FIG. 10.

10. A crystal form of Cl-IPM, characterized in that the crystal form of Cl-IPM meets one of the following conditions: a melting point of 108 to 110 C. as determined by melting point measurements; an endothermic peak at 120 to 128 C., and an endothermic value of 2.5 to 3.5 mW/mg as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern represented by the diffraction angle 2 with characteristic peaks at 23.22, 30.75 and 44.29, with an error not greater than 0.01 as determined by X-ray powder diffraction using Cu-K radiation.

11. The crystal form of Cl-IPM according to claim 10, characterized by an endothermic peak at 124.81 C. (with an error of 1 C.); and an endothermic value of 3.108 mW/mg as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern represented by the diffraction angle 2 with characteristic peaks at 8.02, 16.01, 19.39, 20.51, 22.03, 23.22, 24.26, 24.79, 25.36, 30.75, 32.53, 34.31, 34.50, 37.91 and 44.29, with an error not greater than 0.01 as determined by X-ray powder diffraction using Cu-K radiation.

12. The crystal form of Cl-IPM according to claim 10, characterized in that the crystal form of Cl-IPM meets one of the following conditions: it has the X-ray powder diffraction pattern as shown in FIG. 3; and it has the differential scanning calorimetry pattern as shown in FIG. 4.

13. A method of synthesizing a compound selected from Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, and Compound H: ##STR00096## wherein L is selected from the group consisting of CH.sub.2, CD.sub.2, CH(CH.sub.3), CD(CD.sub.3), CD(CH.sub.3), C(CH.sub.3).sub.2, C(CD.sub.3).sub.2, ##STR00097## Z.sub.3 is selected from the group consisting of ##STR00098## ##STR00099## X in Compound A is Br or Cl; D in the L is deuterium, an isotope of hydrogen; ##STR00100## wherein the definitions of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.8, R.sub.9 and R.sub.10 are as described in the claims of Patent Application PCT/CN2020/089692 (Publication No. WO2020228685A9); ##STR00101## wherein the definitions of Rw are as described in the claims of Patent Application PCT/CN2020/120281 (Publication No. WO2021068952A1); ##STR00102## wherein A is substituted or unsubstituted C.sub.6-C.sub.10 aryl, biaryl or substituted biaryl, or a 5-15 membered heteroaryl or NCR.sup.1R.sup.2, wherein the substituent is selected from the group consisting of halo, CN, NO.sub.2, O(CH.sub.2)O, CO.sub.2H and its salts, OR.sup.100, CO.sub.2R.sup.100, CONR.sup.101R.sup.102, NR.sup.101R.sup.102, NR.sup.100SO.sub.2R.sup.100, SO.sub.2R.sup.100, SO.sub.2NR.sup.101R.sup.102, C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.10 heterocyclyl; wherein R.sup.100, R.sup.101 and R.sup.102 are each independently hydrogen, C.sub.1-C.sub.8 alkyl or C.sub.6-C.sub.12 aryl; or R.sup.101 and R.sup.102 together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclic ring; wherein alkyl and aryl are each substituted with 1-3 halo or 1-3 C.sub.1-C.sub.6; wherein R.sup.1 and R.sup.2 are each independently phenyl or methyl; X, Y and Z are each independently hydrogen or halo; and R is hydrogen or C.sub.1-C.sub.6 alkyl or halogen-substituted alkyl; wherein X in the X-IPM is Cl or Br; ##STR00103## wherein the definitions of R.sub.1, R.sub.2, R.sub.3, and Cx are as described in the claims of Patent Application PCT/CN2020/114519 (Publication No. WO2021120717A1), which corresponds to Chinese Application No. 2020800673113 (Publication No. CN114466853A); ##STR00104## wherein the definitions of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16 and R.sub.17 are as described in the claims of Patent Application PCT/US2016/039092 (Publication No. WO2016210175A1), which corresponds to Chinese Application No. 2016800368985 (Publication No. CN108024974A) ##STR00105## wherein the definitions of R.sub.1, R.sub.2, R.sub.3, R.sub.4 and T are as described in the claims of Patent Application PCT/CN2021/118597 (Publication No. WO2022057838A1), wherein the method uses the X-IPM obtained by the process according to claim 1 as a reactant.

14. The method according to claim 13, wherein Compound A1 is reacted with Compound III to obtain Compound A: ##STR00106## Compound B1 is reacted with Compound III to obtain Intermediate B2, which is subjected to a ring-closure reaction to obtain Compound B: ##STR00107## Compound C1 is reacted with Compound III to obtain Compound III, which is subjected to a ring-closure reaction to obtain Compound C: ##STR00108## Compound D1 is reacted with Compound III to obtain Intermediate D2, which is subjected to a ring-closure reaction to obtain Compound D: ##STR00109## Compound E1 is reacted with Compound III to obtain Intermediate E2, which is subjected to a ring-closure reaction to obtain Compound E: ##STR00110## Compound F1 is reacted with Compound III to obtain Intermediate F2, which is subjected to a ring-closure reaction to obtain Compound F: ##STR00111## Compound G1-3-(I) is reacted with Compound III to obtain Intermediate G2-3-(I), which is subjected to a ring-closure reaction to obtain Compound G-3-(I): ##STR00112## Compound H1 is reacted with Compound III to obtain Intermediate H2, which is subjected to a ring-closure reaction to obtain Compound H: ##STR00113##

15. The method according to claim 13, wherein Compound A is selected from compounds having the following structures: ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## Compound B is selected from compounds having the following structures: ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## Compound C is selected from compounds having the following structures: ##STR00126## ##STR00127## ##STR00128## Compound D is selected from compounds having the following structures: ##STR00129## ##STR00130## ##STR00131## Compound E is selected from compounds having the following structures: ##STR00132## ##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## Compound F is selected from compounds having the following structures: ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## Compound G is selected from compounds having the following structures: ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## Compound H is selected from compounds having the following structures: ##STR00183##

16. A method for detection of HPLC purity of Br-IPM, characterized in that the method uses any one or more of the following detection parameters: a reversed-phase C18 column is used as a chromatographic column for separation; an ultraviolet detector is used for detection, with a detection wavelength of 210 nm; a two-phase eluent is used for elution, with mobile phase A being a 0.1% phosphoric acid solution, and mobile phase B being acetonitrile; and a gradient elution procedure comprises varying the volume percentage of mobile phase A from 90% to 20%, and when the volume percentage of mobile phase A is 20%, isocratic elution is performed for a period of time.

17. The method for detection of HPLC purity according to claim 16, characterized in that the method uses any one or more of the following detection parameters: the chromatographic column used is a Thermo Acclaim 120A C.sub.18 column (250*4.6 mm), and the flow rate of the mobile phases is 0.7 ml/min; and the elution procedure is as follows: TABLE-US-00014 Volume Volume percentage percentage of mobile of mobile Time/min phase A phase B 0 90 10 5 90 10 35 20 80 40 20 80 40.1 90 10 45 90 10 signal peaks of corresponding Br-IPM are detected by the ultraviolet detector within 12-15 minutes.

18. The method according to claim 13, characterized in that the X-IPM is a Br-IPM of a crystal form, characterized in that the crystal form of Br-IPM meets one of the following conditions: a melting point of 106 to 107 C. as determined by melting point measurements; an endothermic peak at 117.5-119.5 C. and an endothermic value of 1.65 to 1.85 mW/mg as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern represented by the diffraction angle 2 with characteristic peaks at 7.77, 15.57 and 19.01, with an error not greater than 0.01 as determined by X-ray powder diffraction using Cu-K radiation.

19. The method according to claim 13, characterized in that the X-IPM is a Cl-IPM of a crystal form, characterized in that the crystal form of Cl-IPM meets one of the following conditions: a melting point of 108 to 110 C. as determined by melting point measurements; an endothermic peak at 120 to 128 C., and an endothermic value of 2.5 to 3.5 mW/mg as determined by differential scanning calorimetry; and an X-ray powder diffraction pattern represented by the diffraction angle 2 with characteristic peaks at 23.22, 30.75 and 44.29, with an error not greater than 0.01 as determined by X-ray powder diffraction using Cu-K radiation.

20. The method for detection of HPLC purity according to claim 16, characterized in that signal peaks of Br-IPM are detected by the ultraviolet detector when the volume percentage of mobile phase A is in the range of 20% to 40%.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0178] FIG. 1 is the .sup.1H-NMR spectrum of the Cl-IPM prepared in Example 1.

[0179] FIG. 2 is the .sup.31P-NMR spectrum of the Cl-IPM prepared in Example 1.

[0180] FIG. 3 is the X-ray powder diffraction pattern of the Cl-IPM prepared in Example 1 (the test was performed using Cu-K at a temperature of 25 C. and a humidity of 35%, the sample was uniformly ground to pass 100 mesh, and the angle of refraction was represented by 20).

[0181] FIG. 4 is the differential scanning calorimetry (DSC) pattern of the Cl-IPM prepared in Example 1 (the test was performed using an Al.sub.2O.sub.3 crucible at a temperature range of 25 C.-410 C. and a heating rate of 10 C./min; the flow rate of the purging nitrogen was 50 ml/min, and the flow rate of the protective nitrogen was 20 ml/min).

[0182] FIG. 5 is the X-ray powder diffraction pattern of the Cl-IPM prepared in Comparative Example 1 (the test was performed using Cu-K at a temperature of 25 C. and a humidity of 35%, the sample was uniformly ground to pass 100 mesh, and the angle of refraction was represented by 20).

[0183] FIG. 6 is the differential scanning calorimetry (DSC) pattern of the Cl-IPM prepared in Comparative Example 1 (the test was performed using an Al.sub.2O.sub.3 crucible at a temperature range of 25 C.-410 C. and a heating rate of 10 C./min; the flow rate of the purging nitrogen was 50 ml/min, and the flow rate of the protective nitrogen was 20 ml/min).

[0184] FIG. 7 is the superimposed X-ray powder diffraction patterns of the Cl-IPM prepared in Example 1 and the Cl-IPM prepared in Comparative Example 1 (the test was performed using Cu-K at a temperature of 25 C. and a humidity of 35%, the sample was uniformly ground to pass 100 mesh, and the angle of refraction was represented by 2), wherein the abscissa indicates 2, the ordinate indicates the peak heights (cts), X represents the pattern of the Cl-IPM prepared in Example 1, and Y represents the pattern of the Cl-IPM prepared in Comparative Example 1.

[0185] FIG. 8 is the HPLC spectrum of the Br-IPM prepared in Experiment Si of Example 2.

[0186] FIG. 9 is the X-ray powder diffraction pattern of the Br-IPM prepared in Experiment Si of Example 2 (the test was performed using Cu-K at a temperature of 25 C. and a humidity of 35%, the sample was uniformly ground to pass 100 mesh, and the angle of refraction was represented by 20).

[0187] FIG. 10 is the differential scanning calorimetry (DSC) pattern of the Br-IPM prepared in Experiment Si of Example 2 (the test was performed using an Al.sub.2O.sub.3 crucible at a temperature range of 25 C.-410 C. and a heating rate of 10 C./min; the flow rate of the purging nitrogen was 50 ml/min, and the flow rate of the protective nitrogen was 20 ml/min).

[0188] FIG. 11 is the X-ray powder diffraction pattern of the Br-IPM prepared in Comparative Example 2 (the test was performed using Cu-K at a temperature of 25 C. and a humidity of 35%, the sample was uniformly ground to pass 100 mesh, and the angle of refraction was represented by 20).

[0189] FIG. 12 is the differential scanning calorimetry (DSC) pattern of the Br-IPM prepared in Comparative Example 2 (the test was performed using an Al.sub.2O.sub.3 crucible at a temperature range of 25 C.-410 C. and a heating rate of 10 C./min; the flow rate of the purging nitrogen was 50 ml/min, and the flow rate of the protective nitrogen was 20 ml/min).

[0190] FIG. 13 shows the superimposed X-ray powder diffraction patterns of the Br-IPM prepared in Experiment Si of Example 2 and the Br-IPM prepared in Comparative Example 2 (the test was performed using Cu-K at a temperature of 25 C. and a humidity of 35%, the sample was uniformly ground to pass 100 mesh, and the angle of refraction was represented by 20), wherein the abscissa indicates 2, the ordinate indicates the peak heights (cts), M represents the pattern of the Br-IPM prepared in Experiment Si of Example 2, and N represents the pattern of the Br-IPM prepared in Comparative Example.

[0191] FIG. 14 is a curve graph showing the change of the content of Br-IPM over time when the Br-IPM prepared in Experiment Si of Example 2 was stored at 5 C., 2-8 C., and 25 C.

EXAMPLES

[0192] The specific implementation of the present invention will be described below through specific examples.

[0193] All the experimental instruments and test conditions involved in the examples of the present application are as follows:

[0194] The instrument for .sup.1H-NMR and .sup.31P-NMR spectroscopy was the German Bruker 400 MHz nuclear magnetic resonance (NMR) spectrometer AVANCE NEO 400 M; the test conditions were that 20 mg of a sample was dissolved in the deuterated reagent DMSO or other suitable solvents, and samples were taken and detected by AVANCE NEO 400 M at 400 HZ.

[0195] The X-ray powder diffraction (XRPD) instrument was Holland PANalytical-XPert 3 Powder; the test was performed using Cu-K at a temperature of 25 C. and a humidity of 35%, the sample was uniformly ground to pass 100 mesh, and the angle of refraction was represented by 20, to obtain X-ray powder diffraction patterns, with an error of <0.01.

[0196] The instruments for differential scanning calorimetry (DSC) were a synchronous thermal analyzer, NETZSCH, Sta-449F3; and the test conditions were that the test was performed using an Al.sub.2O.sub.3 crucible at a temperature range of 25 C.-410 C. and a heating rate of 10 C./min; the flow rate of the purging nitrogen was 50 ml/min, the flow rate of the protective nitrogen was 20 ml/min; and the error range was +1 C. for the temperature and was 5 g for the mass.

Description of the Abbreviations for the Reagents:

[0197] DCM is dichloromethane, TEA is triethylamine, THF is tetrahydrofuran, PPh.sub.3 is triphenylphosphine, DIAD is diisopropyl azodicarboxylate, EtOAc is ethyl acetate, SiO.sub.2 is silicon dioxide, PE is petroleum ether and DIPEA is N,N-diisopropylethylamine.

Description of the Determination of the Yield and HPLC Purity:

[0198] In all the examples and the comparative examples provided by the present application, the amount of 2-haloethylamine hydrohalide was excessive relative to the amount of phosphorus oxyhalide. Therefore, all the yields were calculated based on the phosphorus oxyhalide, and specifically, the yields were obtained by dividing the amount obtained after the post-treatment by the theoretical amount.

Example 1: Preparation of Cl-IPM

[0199] A typical operation of using the new method developed by the present invention for preparing Cl-IPM is as follows.

##STR00084##

[0200] To a 250 ml dry three-necked flask was added 150 ml of dry dichloromethane and 7.2 g (0.0621 mol, 2.1 eq.) 2-chloroethylamine hydrochloride in sequence, the reaction mixture was coolled to 30 C., and 8.6 g (0.0300 mol, 1.0 eq.) phosphorus oxybromide was added. After the addition, the temperature continued to decrease to 70 C., then 8.4 ml (0.0600 mol, 2.0 eq.) of a solution of dry triethylamine dissolved in 20 ml of dry dichloromethane was slowly added dropwise to the reaction mixture, and the rate of the dropwise addition was controlled so that the temperature of the reaction solution did not exceed 70 C.

[0201] After completion of the dropwise addition, the temperature was naturally raised to 60 C. At this temperature, 4.2 ml (0.0300 mol, 1.0 eq.) of a solution of dry triethylamine dissolved in 20 ml of dry dichloromethane was slowly added dropwise to the reaction mixture, and the rate of the dropwise addition was controlled so that the temperature of the reaction solution did not exceed 60 C.

[0202] After completion of the dropwise addition, the temperature was naturally raised to 50 C. At this temperature, 4.2 ml (0.0300 mol, 1.0 eq.) of a solution of dry triethylamine dissolved in 20 ml of dry dichloromethane was slowly added dropwise to the reaction mixture, and the rate of the dropwise addition was controlled so that the temperature of the reaction solution did not exceed 50 C.

[0203] After completion of the dropwise addition, the temperature was naturally raised to 20 C. Filtration was performed. The filter residue was washed with a small amount of dichloromethane, the filtrate and the washing liquid were combined, 10 ml of ice water was added at an external temperature of 0 to 5 C., and rapid stirring was performed for 4 h.

[0204] Suction filtration was performed, and washing with stirring was performed with a small amount of ice water and then with acetone respectively. The filter cake was collected, and vacuum-dried at room temperature to obtain 3.01 g of Cl-IPM as a white solid with a yield of 45.4%.

The Test Results were as Follows:

[0205] Melting point measurement: the melting point was 108 to 110 C.

[0206] .sup.1H-NMR (DMSO-d6, /ppm) data: 2.85-3.08 (4H, m, CH.sub.2), 3.52-3.61 (4H, m, CH.sub.2), as shown in FIG. 1.

[0207] .sup.31P-NMR (DMSO-d6, /ppm) data: 12.305 (PO), as shown in FIG. 2.

[0208] An X-ray powder diffraction test with Cu-K radiation was performed. The primary spectrum represented by 2 is shown in FIG. 3. According to the test conditions of the instrument, peaks with a peak height greater than 8 cts were selected, and the data are listed in Table 3 below:

TABLE-US-00005 TABLE 3 Crystal data of the Cl-IPM prepared in Example 1 Peak Relative Position height intensity (2) (cts) (%) 8.0209 22560.43 100 16.1087 1373.14 6.09 18.7114 296.14 1.31 19.3901 745.01 3.3 20.5104 1185.97 5.26 21.4299 51.5 0.23 22.0369 1751.51 7.76 23.2285 3008.18 13.33 23.8235 337.38 1.5 24.2629 4742.66 21.02 24.7915 1310.07 5.81 25.3655 1077.28 4.78 25.8086 208.68 0.92 28.0429 363.84 1.61 28.4479 119.1 0.53 29.6298 291.83 1.29 29.949 86.4 0.38 30.2621 85.42 0.38 30.7579 792.6 3.51 30.9802 623.98 2.77 32.5394 3283.25 14.55 33.107 478.67 2.12 33.928 455.11 2.02 34.3143 1207.96 5.35 34.503 1875.94 8.32 35.6098 186.33 0.83 37.2134 50.97 0.23 37.914 1274.95 5.65 39.3701 73.9 0.33 40.2372 31.96 0.14 40.713 240.12 1.06 41.0129 352.57 1.56 42.1423 14.33 0.06 42.9436 28.85 0.13 43.6994 38.41 0.17 44.2974 711.95 3.16 45.9149 511.81 2.27 46.9205 64.95 0.29 48.347 8.68 0.04 48.786 17.05 0.08 49.8437 165.77 0.73 50.8707 123.92 0.55 51.1323 103.51 0.46 52.1419 140.36 0.62 53.4125 13.99 0.06 53.9493 35.19 0.16 56.2199 20.18 0.09 57.3457 83.6 0.37 58.0845 26.77 0.12

[0209] A differential scanning calorimetry (DSC) test was performed. The heating program was set as follows: the temperature was initially 25 C. and increased to 410 C. with a gradient of 10 C./min. The endothermic peak of DSC was at 124.81 C., and the endothermic value was 3.108 mW/mg, as shown in FIG. 4.

[0210] In the following comparative example, Cl-IPM was prepared by the method in the patent application CN102746336A, and the yield and the spectral characteristics of the product prepared by the prior art method were measured.

Comparative Example 1: Existing Crystal Forms (or Possibly Amorphous Forms) of the Cl-IPM Prepared by the Prior Art Process

[0211] To a solution of 2-chloroethyl hydrochloride (11.0 g) in DCM (90 mL) at 10 C. was added a solution of POCl.sub.3 (2.3 mL) in DCM (4 mL) followed by addition of a solution of TEA (14.1 mL) in DCM (25 mL). The reaction mixture was filtered, and the filtrate was concentrated to ca. 30% of the original volume and filtered. The residue was washed with DCM (325 mL) and the combined DCM portions were concentrated to yield a solid to which a mixture of THF (6 mL) and water (8 mL) was added. THF was removed in a rotary evaporator, and the resulting solution chilled overnight in a fridge. The precipitate obtained was filtered, washed with water (10 mL) and ether (30 mL), and dried in vacuo to yield 1.70 g of Cl-IPM (it is calculated that the yield is 31.1%).

[0212] Melting point measurement was carried out using the same method as the one for the Cl-IPM obtained in the above Example 1, and the melting point was 104 to 105 C.; an X-ray powder diffraction test was carried out, and the pattern is shown in FIG. 5. According to the test conditions of the instrument, peaks with a peak height greater than 8 cts were selected, and the data are listed in Table 4 below:

TABLE-US-00006 TABLE 4 Crystal data of the Cl-IPM prepared in Comparative Example 1 Peak Relative Position height intensity (2) (cts) (%) 8.0344 34868.45 100 16.125 1845.15 5.29 18.6743 522.78 1.5 19.3757 685.77 1.97 20.4864 1605.75 4.61 21.4225 103.45 0.3 21.9972 2934.48 8.42 23.2294 1645.92 4.72 23.7962 390.7 1.12 24.2994 5792.96 16.61 24.7644 1124.79 3.23 25.3397 1256.03 3.6 25.8062 111.11 0.32 28.0351 316.75 0.91 28.4316 89.68 0.26 29.6204 252.05 0.72 29.9222 123.91 0.36 30.7259 780.78 2.24 30.9534 388.77 1.11 32.0465 8.6 0.02 32.5746 4028.5 11.55 33.0991 365.86 1.05 33.9317 295.24 0.85 34.3025 817.38 2.34 34.4812 1196.54 3.43 35.5951 160.13 0.46 37.1792 8.95 0.03 37.9218 715.12 2.05 39.3761 49.21 0.14 40.1845 27.38 0.08 40.6795 191.27 0.55 41.0464 395.49 1.13 42.8488 21.19 0.06 43.74 61.46 0.18 44.2868 489.97 1.41 45.8951 235.7 0.68 46.0401 212.46 0.61 46.9171 31.58 0.09 48.2566 29.65 0.09 48.7805 19.73 0.06 49.7712 132.17 0.38 50.826 67.45 0.19 51.1168 91.35 0.26 52.1137 108.9 0.31 53.2472 35.25 0.1 54.3662 9.87 0.03 56.1649 13.16 0.04 57.519 34.51 0.1 58.8462 17.67 0.05 59.8687 83.83 0.24

[0213] A differential scanning calorimetry (DSC) test was performed (the heating program: the temperature was initially 25 C. and increased to 410 C. with a gradient of 10 C./min). The endothermic peak of DSC was at 116.04 C., and the endothermic value was 1.017 mW/mg, as shown in FIG. 6.

[0214] After plotting the data in Table 3 and Table 4 of the Cl-IPMs prepared in Example 1 and Comparative Example 1, they were superimposed and compared to show different characteristic peaks so as to obtain the superimposed patterns (by spreadsheet processing) as shown in FIG. 7, wherein the abscissa indicates 2, the ordinate indicates peak heights (cts), the maximum peak height selected on the ordinate is 6,000 cts, X represents the pattern of the Cl-IPM prepared in Example 1, and Y represents the pattern of the Cl-IPM prepared in Comparative Example 1.

[0215] From the superimposed XRPD patterns of the Cl-IPM, it can be seen that the pattern of the crystal form of Cl-IPM prepared by the new process of the present application can basically overlap with that of the existing crystal form (or possibly amorphous form) as prepared by the prior art process, but the characteristic peaks of the new crystal form at corresponding positions are obviously different, as shown in Table 5 below:

TABLE-US-00007 TABLE 5 Comparison of the characteristic peaks of the Cl-IPM Exsiting crystal form or New crystal form amorphous form of Cl-IPM of Cl-IPM (characteristic peaks, (characteristic peaks, represented by 2) represented by 2) 23.22 24.30 30.75 32.57 44.29 44.29

[0216] Further, the relatively obvious characteristic peaks were observed also at 8.02, 16.01, 19.39, 20.51, 22.03, 24.26, 24.79, 25.36, 32.53, 34.31, 34.50 and 37.91, with an error range not greater than 0.01 for each characteristic peak.

[0217] The DSC data were further compared. FIG. 4 is the DSC pattern of the crystal form of Cl-IPM prepared by the new process of the present application, and FIG. 6 is the DSC pattern of the existing crystal form (or possibly amorphous form) prepared by the prior art process. Evidently, they were siginificantly different in term of both the endothermic peaks and endothermic values.

[0218] The melting points were measured. The melting point of the crystal form of Cl-IPM prepared by the new process of the present application was 108-110 C., and the melting point of the existing crystal form (or possibly amorphous form) prepared by the prior art process was 104-105 C.

[0219] By comparing the XRPD patterns, DSC data, and melting points, it can be seen that the crystal form of Br-IPM prepared by the new process of the present application is completely different from the existing crystal form (or possibly amorphous form) prepared by the prior art process, and is anew crystal form.

Example 2: Preparation of Br-IPM

[0220] A typical operation of using the new method developed by the present invention for preparing Br-IPM is as follows.

##STR00085##

Experiment No. S1:

[0221] 35 ml of dichloromethane and 5.43 g of 2-bromoethylamine hydrobromide was added into a 100 ml three-necked flask (under nitrogen atmosphere) at room temperature. Stirring was started and the temperature was set to drop to 60 C. When the temperature dropped to about 20 C., 3.80 g of phosphorus oxybromide was added, and the temperature continued to drop to 60 C.

[0222] A solution of triethylamine in dichloromethane was added in three batches successively.

[0223] For the first addition, a mixed solution consisting of 2.86 g triethylamine and 3.9 ml dichloromethane was added dropwise at a temperature ranging from 60 C. to 55 C., and the rate of the dropwise addition was mainly controlled by the temperature to be relatively moderate; [0224] for the second addition, a mixed solution consisting of 1.43 g triethylamine and 3.9 ml dichloromethane was added dropwise at a temperature ranging from 55 C. to 50 C., and the rate of addition was controlled to be relatively slow; and [0225] for the third addition, a mixed solution consisting of 1.14 g triethylamine and 3.9 ml dichloromethane was added dropwise at a temperature ranging from 45 C. to 40 C., and the rate of addition was controlled to be slow.

[0226] After the addition of the solution of triethylamine in dichloromethane, the temperature was slowly raised to 20 C. naturally, 12 ml of water was slowly added dropwise, the temperature was slowly raised to 5 C., and while this temperature was maintained, stirring was continued for 8 h.

[0227] A solid filter cake was obtained by suction filtration. The solid was washed by beating twice with a total of 40 ml of water, once with 32 ml of dichloromethane, and once with 32 ml of acetone, and was vacuum-dried at room temperature for 12 h to obtain 1.9 g of Br-IPM as a solid with a yield of 46.6%, and HPLC purity of 97.08%. The HPLC pattern is shown in FIG. 8.

[0228] The conditions for determination of HPLC purity of the Br-IPM are as follows:

TABLE-US-00008 Preferred chromatographic conditions for determination of purity of the Br-IPM Chromatographic column: Thermo Acclaim 120A C18 250*4.6 mm, 5 m Flow rate: 0.7 ml/min Detection wavelength: 210 nm Column temperature: 5 C. Mobile phase A: 0.1% phosphoric acid solution Mobile phase B: acetonitrile Elution procedure: Time A % B % 0 90 10 5 90 10 35 20 80 40 20 80 40.1 90 10 45 90 10

[0229] The results in FIG. 8 show that the Br-IPM showed a peak at 13.427 min. After many times of actual testing, it was found that due to the influence of conditions such as the temperature and instrument, it is normal when the time at which the Br-IPM showed a peak was within a range of 12 to 15 min.

[0230] The results of melting point measurements, X-ray powder diffraction and differential scanning calorimetry are as follows: [0231] Melting point: 106-107 C.

[0232] XRPD: Cu-K radiation. The primary spectrum represented by 2 is shown in FIG. 9. According to the test conditions of the instrument, the peak heights greater than 25 cts were selected, and the data are listed in Table 6 below:

TABLE-US-00009 TABLE 6 Crystal data of the Br-IPM prepared in Experiment S1 of Example 2 Peak Relative Position height intensity (2) (cts) (%) 3.5967 77.32 0.82 7.7772 3061.84 32.6 12.1484 130.42 1.39 14.7103 53.61 0.57 15.5768 1410.41 15.02 17.0987 52.82 0.56 18.705 655.28 6.98 19.0179 1170.98 12.47 20.3334 877.53 9.34 21.9302 3045.02 32.42 22.7161 4435.18 47.22 23.4525 9392.62 100 23.8415 1801.87 19.18 24.4215 958.9 10.21 25.0523 2499.45 26.61 25.6369 97.73 1.04 27.4451 1512.8 16.11 27.9992 947.74 10.09 28.8466 217.95 2.32 29.0452 498.29 5.31 29.4314 198.78 2.12 29.657 229.98 2.45 30.005 610.06 6.5 30.1327 602.14 6.41 30.4321 1706.9 18.17 31.4206 7033.43 74.88 31.8228 378.65 4.03 32.1247 218.82 2.33 32.683 521.39 5.55 32.8471 616.34 6.56 33.4052 1678.02 17.87 33.752 2890.69 30.78 35.2065 315.34 3.36 35.8699 53.59 0.57 36.7837 2070.73 22.05 37.2294 211.96 2.26 37.912 51.88 0.55 38.5127 137.41 1.46 39.5584 1341.7 14.28 39.6926 769.86 8.2 40.1734 348.92 3.71 40.7581 420.48 4.48 41.6069 61.41 0.65 42.109 210.96 2.25 42.4733 33.62 0.36 43.0389 1407.52 14.99 43.1753 688.13 7.33 43.5485 181.83 1.94 44.0799 29.56 0.31 44.5334 262.51 2.79 44.9706 1049.42 11.17 45.8386 119.32 1.27 47.6617 214.19 2.28 48.7488 290.19 3.09 49.5326 194.19 2.07 50.0486 87.47 0.93 50.5206 685.8 7.3 50.6787 432.29 4.6 51.3793 194.67 2.07 52.0373 117.11 1.25 52.6772 289.24 3.08 53.9127 79.13 0.84 55.0512 97.28 1.04 55.4652 549.42 5.85 56.5306 167.51 1.78 57.2745 64.11 0.68 57.9727 297.85 3.17 58.2487 502.22 5.35 58.4357 493.72 5.26 59.3446 25.92 0.28

[0233] A DSC test was performed (the heating program: the temperature was initially 25 C. and increased to 410 C. with a gradient of 10 C./min): the endothermic peak of DSC was 118.41 C., and the endothermic value was 1.75 mW/mg, as shown in FIG. 10.

[0234] The process of preparing Br-IPM using the new method developed by the present invention was repeated and scaled up based on the aforementioned typical operating conditions. The experiments were as follows:

Experiment Nos. S2-S6

[0235] A series of experiments were conducted to prepare Br-IPM with different amounts of the raw materials under the same experimental conditions as in Experiment No. S1 in Example 2, except that the amounts of the raw materials phosphorus oxybromide, 2-bromoethylamine hydrobromide and triethylamine, and the ratio of dichloromethane as a solvent and the solute dissolved therein were varied. The experimental conditions and the experimental results are shown in Table 7.

TABLE-US-00010 TABLE 7 Experimental results of preparing Br-IPM with different amounts of the raw materials The ratio of the The mass The Phosphorus amounts of the of the yield Experiment 2-Bromoethylamine oxybromide Triethylamine three additions obtained of HPLC No. hydrobromide (g) (g) (ml or g) of triethylamine Br-IPM (g) Br-IPM purity S1 5.43 3.80 5.43 g 1:0.5:0.4 1.9 46.6% 97.08% S2 12.81 8.96 12.82 g 1:0.5:0.5 5.0 51.6% 95.97% S3 17.47 13.98 28 ml 1:0.5:0.4 7.86 52.0% 95.83% S4 1500 1000 1900 ml 1:0.5:0.4 670.9 62.1% 93.23% S5 1530 970 1890 ml 1:0.5:0.4 642 61.2% 93.96% S6 3711 2360 4590 ml 1:0.5:0.4 1647 64.6% 94.83%
Experiment No. S4:

[0236] 9.0 L of dichloromethane and 1.5 kg of 2-bromoethylamine hydrobromide were added into a 20 ml reaction kettle (under nitrogen atmosphere) at room temperature. Stirring was started and the temperature was set to drop to 60 C. When the temperature dropped to about 20 C., 1.0 kg of phosphorus oxybromide was added, and the temperature continued to drop to 60 C.

[0237] A solution of triethylamine in dichloromethane was added in three batches successively.

[0238] For the first addition, a mixed solution consisting of 1 L triethylamine and 1 L dichloromethane was added dropwise at a temperature ranging from 60 C. to 55 C., and the rate of the dropwise addition was mainly controlled by the temperature to be relatively moderate; [0239] for the second addition, a mixed solution consisting of 0.5 L triethylamine and 1 L dichloromethane was added dropwise at a temperature ranging from 55 C. to 50 C., and the rate of addition was controlled to be relatively slow; and [0240] for the third addition, a mixed solution consisting of 0.4 L triethylamine and 1 L dichloromethane was added dropwise at a temperature ranging from 45 C. to 40 C., and the rate of addition was controlled to be slow.

[0241] After the addition of the solution of triethylamine in dichloromethane, the temperature was slowly raised to 20 C. naturally, 3 L of water was slowly added dropwise, the temperature was slowly raised to 5 C., and while this temperature was maintained, stirring was continued for 8 h.

[0242] A solid filter cake was obtained by suction filtration. The solid was washed by beating twice with a total of 10 L of water, once with 8 L of dichloromethane, and once with 8 L of acetone, and was vacuum-dried at room temperature for 12 h to obtain 670.9 g of Br-IPM as a solid with a yield of 62.1% and HPLC purity of 93.23%.

[0243] In the aforementioned embodiments S1 to S6 (S1 is a typical operation of the new process provided by the present invention for synthesizing Br-IPM), Br-IPM was systhsized by changing the conditions such as the amounts of the raw materials such as phosphorus oxybromide, 2-bromoethylamine hydrobromide and triethylamine, with the final yield ranging from 46% to 65%, and HPLC purity ranging from 93% to 97%, which were basically stable. Therefore, it can be considered that the present synthesis process is relatively stable, achieves yields and purities which meet the requirements even if the conditions change within a certain range, and is suitable for large-scale industrial production.

[0244] In the following comparative example, Br-IPM was prepared by the method of patent application CN102746336A, and the yield and the spectral characteristics of the product prepared by the prior art method were measured.

Comparative Example 2: Existing Crystal Forms (or Possibly Amorphous Forms) of the Br-IPM Prepared by the Prior Art Process

[0245] To a solution of 2-bromoethylammonium bromide (19.4 g) in DCM (90 mL) at 10 C. was added a solution of POCl.sub.3 (2.3 mL) in DCM (4 mL) followed by addition of a solution of TEA (14.1 mL) in DCM (25 mL). The reaction mixture was filtered, and the filtrate was concentrated to ca. 30% of the original volume and filtered. The residue was washed with DCM (325 mL) and the combined DCM portions were concentrated to yield a solid to which a mixture of THF (6 mL) and water (8 mL) was added. THF was removed in a rotary evaporator, and the resulting solution chilled overnight in a fridge. The precipitate obtained was filtered, washed with water (10 mL) and ether (30 mL), and dried in vacuo to yield 2.1 g of Br-IPM (it is calculated that the yield is 27.46% and the HPLC purity is 93.1%).

[0246] Melting point measurement was carried out using the same method as the one for the Br-IPM obtained in Experiment S1 in the above Example 2, and the melting point was 101 to 103 C.; an X-ray powder diffraction test was carried out, and the pattern is shown in FIG. 11. According to the test conditions of the instrument, peaks with a peak height greater than 40 cts were selected, and the data are listed in Table 8 below:

TABLE-US-00011 TABLE 8 Crystal data of the Br-IPM prepared in Comparative Example 2 Peak Relative Position height intensity (2) (cts) (%) 7.6952 1767.42 17.97 12.0557 104.19 1.06 14.5928 50.64 0.51 15.4945 1367.59 13.91 17.0195 47.42 0.48 18.6168 619.07 6.3 18.93 1322.19 13.44 20.2419 893.29 9.08 20.5738 46.84 0.48 21.8454 2860.53 29.09 22.6332 4371.6 44.45 23.3678 9834.13 100 23.7601 1644.62 16.72 24.3399 954.02 9.7 24.9715 2293.55 23.32 25.5581 69.81 0.71 27.3681 1618.71 16.46 27.9174 988.25 10.05 28.7731 204.9 2.08 28.9632 501.9 5.1 29.3561 258.36 2.63 29.5761 240.11 2.44 29.9238 593.54 6.04 30.0587 649.51 6.6 30.3456 1643.73 16.71 31.3401 7388.14 75.13 31.7606 225.57 2.29 32.0329 201.5 2.05 32.6082 435.01 4.42 32.789 562.93 5.72 33.3231 1789.42 18.2 33.6759 2841.74 28.9 35.129 278.41 2.83 35.8262 56.21 0.57 36.7076 2152.84 21.89 37.1477 165.19 1.68 37.8252 55 0.56 38.4561 158.34 1.61 39.4801 1344.92 13.68 39.9548 328.75 3.34 40.0895 322.61 3.28 40.7004 402.63 4.09 41.5067 41.51 0.42 41.9471 165.35 1.68 42.3526 48.32 0.49 42.9622 1547.66 15.74 43.1034 741.49 7.54 43.4764 208.39 2.12 44.0403 54.58 0.56 44.4552 324.83 3.3 44.8974 997.71 10.15 45.7494 112.05 1.14 47.5011 198.08 2.01 48.6754 287.96 2.93 49.4705 174.15 1.77 49.9181 64.4 0.65 50.4434 730.37 7.43 50.6068 378.37 3.85 51.3033 206.62 2.1 51.9663 164.34 1.67 52.5073 250.68 2.55 52.6157 326.37 3.32 53.8646 83.46 0.85 54.8421 74.48 0.76 54.982 100.75 1.02 55.393 677.79 6.89 55.5669 282.62 2.87 56.4824 205.63 2.09 57.886 296.4 3.01 58.1684 483.39 4.92 58.3654 544.17 5.53

[0247] A differential scanning calorimetry (DSC) test was performed (the heating program: the temperature was initially 25 C. and increased to 410 C. with a gradient of 10 C./min). The endothermic peak of DSC was 120.47 C., and the endothermic value was 1.468 mW/mg, as shown in FIG. 12.

[0248] After plotting the data in Table 6 and Table 8 of the Br-IPM prepared in Experiment S1 in Example 2 and Comparative Example 1, they were superimposed and compared to show different characteristic peaks so as to obtain the superimposed patterns (by spreadsheet processing) as shown in FIG. 13, wherein the abscissa indicates 2, the ordinate indicates peak heights (cts), M represents the pattern of the Br-IPM prepared in Experiment S1 in Example 2, and N represents the pattern of the Br-IPM prepared in Comparative Example 2.

[0249] From the superimposed XRPD patterns of the Br-IPM, it can be seen that the pattern of the crystal form of Br-IPM prepared by the new process of the present application can basically overlap with that of the existing crystal form (or possibly amorphous form) prepared by the prior art process, but the characteristic peaks of the new crystal form at corresponding positions are obviously different, as shown in Table 9 below:

TABLE-US-00012 TABLE 9 Comparison of characteristic peaks of the Br-IPM New crystal form Exsiting crystal form or of Br-IPM amorphous form of Br-IPM (characteristic peaks, (characteristic peaks, represented by 2) represented by 2) 7.77 7.69 15.57 15.49 19.01 18.93

[0250] Further, the relatively obvious characteristic peaks were observed at 21.93, 22.71, 23.45, 23.84, 24.42, 25.05, 27.44, 27.99, 30.43, 31.42, 33.40, 33.75, 36.78, 39.55, 43.03 and 44.97, with an error range not greater than 0.01 for each characteristic peak.

[0251] The DSC data were further compared. FIG. 10 is the DSC pattern of the crystal form of Br-IPM prepared by the new process of the present application, and FIG. 12 is the DSC pattern of the existing crystal form (or possibly amorphous form) prepared by the prior art process. Evidently, they are notably different in terms of both the endothermic peaks and endothermic values.

[0252] The melting points were measured. The melting point of the crystal form of Br-IPM prepared by the new process of the present application was 106-107 C., and the melting point of the existing crystal form (or possibly amorphous form) prepared by the prior art process was 101-103 C.

[0253] By comparing the XRPD patterns, DSC data, and melting points, it can be seen that the crystal form of Br-IPM prepared by the new process of the present application is completely different from the existing crystal form (or possibly amorphous form) prepared by the prior art process, and is anew crystal form.

Comparison of the Examples and Comparative Examples

[0254] The above experiments can also show that compared with the batchwise addition, adding triethylamine in a single addition to the reaction system may lead to too many by-products, thereby leading to extremely low yields. The present application adopts the method of adding triethylamine in batches to prepare Br-IPM or Cl-IPM, both with yields significantly higher than those in the prior art CN102746336A.

[0255] A comparison of the post-treatments of the experimental operations can fully explain the specific reasons why the crystal form of Br-IPM prepared by the new process of the present application is completely different from the existing crystal form (or possibly amorphous form) prepared by the prior art process.

[0256] Both the crystal forms of Br-IPM and Cl-IPM in Comparative Examples 1 and 2 were obtained by concentrating dichloromethane to obtain a solid, dissolving the solid in a mixed solution of THF and water for the second time, removing the THF by rotary evaporation, then cooling the remaining solution overnight in a refrigerator and filtering the solution. In other words, the crystal forms were obtained by heating and concentrating dichloromethane, and precipitating the crystals from the THF-water solution system for the second time by rapid cooling.

[0257] The crystal form of Cl-IPM in Example 1 was formed by adding ice water to the dichloromethane system at 0-5 C., and slowly precipitating the crystals under continuous stirring. The crystal form of Br-IPM in Experiment S1 in Example 2 was 40 formed by adding water to the reaction system at 20 C., raising the temperature to 5 C., and slowly precipitating the crystals with continuous stirring. In other words, in the present application, the crystal forms were obtained by adding ice water to dichloromethane to change the solubility, and slowly precipitating the crystals under stirring.

[0258] In the following Comparative Examples 3 and 4, a similar method to that in Example 1 was employed for preparing Cl-IPM, except for the means of adding the solution of triethylamine in dichloromethane: in Example 1, it was added in three batches, whereas in Comparative Example 3, the solution of triethylamine in dichloromethane in the same amount was added in a single addition.

Comparative Example 3: Preparation of Cl-IPM by Adding Triethylamine in a Single Addition

[0259] To a 250 ml dry three-necked flask was added 150 ml of dry dichloromethane and 7.2 g (0.0621 mol, 2.1 eq.) 2-chloroethylamine hydrochloride in sequence, the reaction mixture was coolled to 30 C., and 8.6 g (0.0300 mol, 1.0 eq.) phosphorus oxybromide was added. After the addition, the temperature continued to decrease to 70 C., then a solution of 16.8 ml (0.1200 mol, 4.0 eq.) of dry triethylamine dissolved in 60 ml of dry dichloromethane was added dropwise to the reaction mixture in a single addition (the solution of triethylamine in dichloromethane was added in a single addition in the same temperature control zone), and the rate of the dropwise addition was controlled so that the temperature of the reaction solution was between 70 C. and 50 C.

[0260] After completion of the dropwise addition, the temperature was naturally raised to 20 C. Filtration was performed. The filter residue was washed with a small amount of dichloromethane, the filtrate and the washing liquid were combined, 10 ml of ice water was added at an external temperature of 0 to 5 C., and rapid stirring was performed for 4 h.

[0261] Suction filtration was performed, and washing with stirring was performed with a small amount of ice water and then acetone respectively. The filter cake was collected, and vacuum-dried at room temperature to obtain 2.30 g of Cl-IPM as a white solid with a yield of 34.7%.

[0262] With other experimental conditions being equal, adding the solution of triethylamine in dichloromethane in a single addition leads to a significantly lower yield than adding the solution in three batches.

[0263] In the following Comparative Example 4, a similar method to that in Experiment S1 in Example 2 was employed for preparing Br-IPM, except for the means of adding the solution of triethylamine in dichloromethane: in Experiment S1 in Example 2, it was added in three batches, whereas in Comparative Example 4, the solution of triethylamine in dichloromethane in the same amount was added in a single addition.

Comparative Example 4: Preparation of Br-IPM by Adding Triethylamine in a Single Addition

[0264] 9.0 L of dichloromethane and 1.5 kg of 2-bromoethylamine hydrobromide were added into a 20 L reaction kettle (under nitrogen atmosphere) at room temperature. Stirring was started and the temperature was set to drop to 60 C. When the temperature dropped to about 20 C., 1.0 kg of phosphorus oxybromide was added, and the temperature continued to drop to 60 C. Then, a mixed solution containing 1.9 L of triethylamine and 3 L of dichloromethane was added dropwise to the reaction mixture in a single addition (the solution of triethylamine in dichloromethane was added in a single addition in the same temperature control zone), and the rate of the dropwise addition was controlled so that the temperature of the reaction system was between 60 C. and 40 C.

[0265] After the addition of the solution of triethylamine in dichloromethane, the temperature was slowly raised to 20 C. naturally, 3 L of water was slowly added dropwise, the temperature was slowly raised to 5 C., and while this temperature was maintained, stirring was continued for 8 h.

[0266] A solid filter cake was obtained by suction filtration. The solid was washed by beating twice with a total of 10 L of water, once with 8 L of dichloromethane, and once with 8 L of acetone, and was vacuum-dried at room temperature for 12 h to obtain 350.1 g of Br-IPM as a solid with a yield of 32.4% and HPLC purity of 93.4%.

[0267] With other experimental conditions being equal, adding the solution of triethylamine in dichloromethane in a single addition leads to a significantly lower yield than adding the solution in three batches.

Example 3

[0268] A study on the stability of the crystal form of Br-IPM obtained in Experiment S1 in the above Example 2 was carried out as follows.

[0269] Samples of the Br-IPM crystals obtained in Experiment S1 in Example 2 were taken, and stored in environments of 5 C., 2-8 C., 25 C. and 40 C. respectively. On different days, samples were taken at the same time for analysis and detection of related substances, and their contents were recorded. The experimental results are shown in Table 10.

TABLE-US-00013 TABLE 10 Detection results of the Br-IPM content in the analysis of related substances Time 25 C. 2-8 C. 5 C. 40 C. (day) (%) (%) (%) (%) 0 93.23 93.23 93.23 93.23 3 94.17 93.28 94.65 86.36 4 94.89 95.06 95.12 Detection was stopped 5 94.53 94.29 94.07 N/A 6 94.32 94.56 95.48 N/A 7 93.86 95.57 94.96 N/A 10 94.64 95.17 95.03 N/A 11 95.25 95.07 95.50 N/A 12 94.97 95.07 95.04 N/A 13 95.28 95.44 95.23 N/A 14 94.61 95.25 95.28 N/A 17 94.75 95.76 95.07 N/A 21 93.81 95.19 95.30 N/A 28 94.01 96.22 94.83 N/A 35 91.42 95.09 94.64 N/A Note: N/A means not detected.

[0270] In the table above, when the Br-IPM crystals were stored at 40 C., their Br-IPM content decreased significantly over time, and the detection was stopped on the third day, indicating that the Br-IPM crystals were unstable when placed at 40 C.

[0271] The detetion data on the Br-IPM contents of the samples stored at 25 C., 5 C. and 2-8 C. were plotted to obtain curves of change of the Br-IPM contents with time at different temperatures, as shown in FIG. 14. As can be seen from the figure, when Br-IPM crystals were stored at 25 C., they were relatively stable for the first 28 days, and subsequently, their Br-IPM content decreased significantly. When Br-IPM crystals were stored at low temperatures of 2-8 C. and 5 C., the Br-IPM content remained relatively stable until the 35th day, indicating that the Br-IPM crystals were suitable for storage at low temperatures and were relatively stable.

[0272] Therefore, the Br-IPM crystals prepared by the new process of the present application are relatively stable, can be stored at room temperature for 28 days, can be stored at 2 to 8 C. and 5 C. for at least 35 days, are suitable as intermediates, and can be stored in factories without the need of directly producing Cl-IPM or Br-IPM in a reaction vessel before its direct participation in the reaction for the preparation of the next intermediate/finished product, as required in the prior art CN102746336A, WO2020228685A9, WO2021068952A1 and the like.

[0273] Because the reagents such as phosphorus oxychloride and phosphorus oxybromide used in the reaction to generate Cl-IPM and Br-IPM are highly toxic and easily react with water, there are relatively high requirements for the sealing properties of the reaction vessel, water removal during operation, and control of moisture content. In large-scale factory production, differences in water content of different batches of phosphorus oxychloride and phosphorus oxybromide, and differences in water removal operations will make the product quality unstable and make it hard to control the quality of the final product. Using the new crystal forms prepared by the present invention, it is possible to prepare a sufficient amount at once to enable the production of compounds with multiple structures (drugs with structures A, B, C, D and E) as desired, which contributes to the quality control of the product.

Example 4

[0274] The following illustrates the typical exemplary reactions for further synthesizing and preparing Compounds A, B, C, D, and E using the Cl-IPM or Br-IPM prepared by the present invention.

Preparation of Compounds 1 and 2

##STR00086##

[0275] When L is CH.sub.2, Z.sub.3 is

##STR00087##

and Z.SUB.3.-L-OH is

##STR00088##

Compound A has the typical structure of Compound 1, which is synthesized by the following method:

##STR00089##

[0276] To a solution of N-methyl-2-nitroimidazole-5-methanol (180 mg, 1.14 mmol), triphenylphosphine (300 mg, 1.14 mmol), and Cl-IPM (127 mg, 0.57 mmol) in THF (10 ml), diisopropyl azodicarboxylate (DIAD, 0.22 ml, 1.14 mmol) was added dropwise at room temperature. After two hours reaction mixture was concentrated and the residue was separated by flash chromatography with 30-100% acetone in toluene to obtain Compound 1.

[0277] Using a similar synthesis method, when Z.sub.3-L-OH is selected from

##STR00090##

Compound 2 can be prepared.

Preparation of Compound 3

##STR00091##

[0278] To a mixture of Compound 3-a (1.44 g, 7.78 mmol), Br-IPM (2.88 g, 9.34 mmol) and PPh.sub.3 (3.06 g, 11.67 mmol) in THF (60 mL) at 0 C. was added DIAD (2.34 g, 11.67 mmol). The mixture was stirred at 0 C. for 1.5 h, concentrated under reduced pressure and purified via FCC (silica gel, EtOAc/Hexane) to afford Compound 3 as a light yellow oil (1.0 g, 27% yield).

Preparation of Compound 4

##STR00092##

[0279] To a mixture of Compound 4-1, Br-IPM and PPh.sub.3 in THF at 0 C. was added DIAD. The mixture was reacted with stirring at 0 C. for 2 h. The reaction mixture was concentrated and purified by chromatography to obtain Compound 4-2.

[0280] Compound 4-2 was dissolved in THF, silver oxide was added, and the mixture was reacted with stirring at 70 C. for 12 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude filter cake product was purified by column chromatography (SiO.sub.2, PE: EtOAc=5:1-1:4) to obtain Compound 4.

Preparation of Compound 5

##STR00093##

[0281] To a mixture of Compound 5-1, Br-IPM and PPh.sub.3 in THF at 5 C. was added DIAD. The mixture was reacted with stirring at 5 to 0 C. for 2.5 h. The reaction mixture was concentrated and purified by chromatography to obtain Compound 5-2.

[0282] Compound 5-2 was dissolved in THF, silver oxide was added, and the mixture was reacted with stirring at 60 C. for 14 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude filter cake product was purified by high-performance liquid chromatography to obtain Compound 5.

[0283] The purification conditions were as follows: [0284] Separation column: Waters Xbridge (size: C18 150*50 mm, particle size: 10 m); [0285] Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; [0286] Elution gradient: 17%-47%, 10 minutes.

Preparation of Compound 6

##STR00094##

[0287] To a mixture of Compound 6-1, Br-IPM and PPh.sub.3 in THF at 10 C. was added DIAD. The mixture was reacted with stirring at 10 to 0 C. for 2.5 h. After the reaction was complete, the temperature was naturally raised to 0 C., and a saturated aqueous solution of ammonium chloride was added dropwise. Extraction was performed with dichloromethane followed by drying, concentration, and column separation (200-300 mesh silica gel, n-heptane: EA=1:1-100) to obtain Compound 6-2.

[0288] Under the protection of nitrogen, Compound 6-2 was dissolved in THF. Then, silver oxide and DIPEA were added. The temperature was increased to 65 C. Reaction was performed for 3 h with stirring. After the reaction was complete, the temperature was reduced to room temperature. Suction filtration through celite was performed followed by washing with dichloromethane. The mother liquor was concentrated. Crystallization was performed by adding a small amount of anhydrous ether, and suction filtration was performed to obtain Compound 6.

[0289] The above examples are just exemplary embodiments of the reactions. In practice, DIAD+PPh.sub.3 in the first step of dehydration condensation of X-IPM is a set of universal and mild reagents for dehydration condensation, and other combinations such as DEAD+PPh.sub.3, DCC+PPh.sub.3 and EDC+PPh.sub.3 can also be used depending on the reactants.

[0290] In the second step of cyclization reaction, silver oxide was used as a catalyst for cyclization in the examples, but in practice, silver nitrate can also be used as the catalyst. DIPEA was used as an acid-binding agent. An acid-binding agent is generally an alkaline substance, and carbonates such as K.sub.2CO.sub.3, organic amines such as triethylamine and diethylamine can all serve as acid-binding agents, or a large amount of pyridine can be directly used (both as a reaction solvent and as an acid-binding agent).

[0291] The above examples describe the basic principles or main features or advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above-mentioned examples, which merely describe the principles or main features or advantages of the present invention together with the specification. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention, and all such changes and modifications fall within the scope of the claims.