Description:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of pharmaceutical compositions, and in specific relates to a compound and a method of preparing the compound in connection with individuals infected with human immunodeficiency virus (HIV).
Background of the invention:
[0002] Human immunodeficiency virus infection leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently an estimated over thirty-five million individuals worldwide suffer from HIV infection.

[0003] Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV infection. There are at least twenty-five drugs that are approved over six different inhibitor classes, which have greatly increase patient survival and quality of life. However, additional therapies are still required due to a number of issues including, but not limited to, undesirable drug-drug interactions, drug-food interactions, non-adherence to therapy, drug resistance due to mutation of the enzyme target, and inflammation related to the immunologic damage caused by the HIV infection.

[0004] Currently, highly active antiretroviral therapy (HAART) is widely used treatment for nearly all HIV-positive patients. HAART consists of therapeutic regimens of antiretroviral medication combinations. However, HAART treatments are complicated as a patient has to get a variety of medications on a regular basis to prevent the rapid emergence of drug-resistant HIV variations. HAART has improved patient survival, but treatment resistance can still develop, and survival and quality of life remain still subpar compared to those of uninfected people.

[0005] Modern antiretroviral therapy (ART) has the ability to effectively suppress HIV replication and improve health outcomes for HIV-infected persons. However, ART cannot completely eliminate HIV viral reservoirs within the individual. HIV genomes can remain latent within mostly immune cells in the infected individual and can reactivate at any time.

[0006] In some cases, the viral reservoir is eliminated during treatment of leukemia and no viral rebound is observed during several years of follow-up. Hence, reduction or elimination of the viral reservoir may be possible and can lead to viral remission or cure. As such, ways have been pursued to eliminate the viral reservoir, by direct molecular means, or to induce reactivation of the latent reservoir during ART so that the latent cells are eliminated. Induction of the latent reservoir typically results in either direct death of the latently infected cell or killing of the induced cell by the immune system after the virus is made visible. As this is performed during ART, viral genomes produced are believed to not result in the infection of new cells and the size of the reservoir may decay.

[0007] Reactivation of latent HIV is believed to be achieved by several means, typically by broad and potent mechanisms of cellular activation and enhancement of anti-HIV immunity. These reactivators and immune-modulators can be specific to certain cell types, such as anti-CD3/anti-CD28 antibodies that will specifically target T cells, or can be non-specific, such as protein kinase C (PKC) agonists that can activate many cell types. The immune-modulatory activities or immune enhancement of innate and adaptive anti-HIV immune responses may depend and vary upon the mechanism of action and level of target engagement. Further, at present there are no drug that can control HIV with both NRTI and PI activity.

[0008] Therefore, there is a need for a composition for antiretroviral therapy (ART) drug with characteristics of nucleoside reverse transcriptase inhibitors (NRTI) and protases inhibitor(PI).
Objectives of the invention:
[0009] The primary objective of the invention is to provide a composition for antiretroviral therapy (ART) drug with characteristics of nucleoside reverse transcriptase inhibitors (NRTI) and protases inhibitor(PI).

[0010] The other objective of the invention is to provide a synthetic method for synthesis of antiretroviral therapy (ART) drug that can be used to control HIV with both NRTI and PI activity.
Summary of the invention:
[0011] The present disclosure proposes a composition for antiretroviral therapy (art) and method of preparing the same. The following presents a simplified summary in order to provide a basic understanding of some aspects of the claimed subject matter. This summary is not an extensive overview. It is not intended to identify key/critical elements or to delineate the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.

[0012] In order to overcome the above deficiencies of the prior art, the present disclosure is to solve the technical problem to provide a compound and a method of preparing the compound in connection with individuals infected with human immunodeficiency virus (HIV).

[0013] According to an aspect, the invention provides a formula (IX) for antiretroviral therapy (ART). The formula (IX) is thiazol-5-ylmethyl ((2S,3S,5S) -5- ((((1S,4R) -4- (2-amino-6-(cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1-yl) methyl) amino) -3-hydroxy-1,6- diphenylhexan-2-ylcarbamate.

[0014] According to another aspect, the invention provides a preparation method for the formula (IX). First, N- (2-amino-4-chloro-6- (((1R,4S) -4- (hydroxymethyl) cyclopent-2-en-1- yl) amino) pyrimidin-5-yl) formamide is added to triethyl ortho formate in an ethanol and HCl medium to obtain ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol. Next, the ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol is filtered to obtained a crude ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol.

[0015] Next, the crude ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol is crystalized at pH 7 with 10% NaHCO3 solution to obtain a crystalized ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol. Later, the crystalized ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol is purified with column by 9:1 of hexane and ethyl acetate to obtain a purified ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol.

[0016] Next, the purified ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol is added to cyclopropyl amine in isopropyl alcohol(IPA) medium in presence of NaHCO3 at a temperature 82⁰C to obtain ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol. Later, ((1S,4R) -4- (2-amino-6-(cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol is filtered to obtained a crude ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol.

[0017] Next, the crude ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol is crystalized with isopropanol (IPA) solution to obtain a crystalized ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol. Later, the crystalized ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl)cyclopent-2-en-1- yl) methanol is purified with column by 6:4 of hexane and ethyl acetate to obtain a purified ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol.

[0018] Next, the purified ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol is added to SOCl2 in isopropyl alcohol(IPA) medium in presence of dimethyl formamide (DMF) in dichloro methane (DCM) medium at a temperature 200C to obtain 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine. Later, the 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine is filtered to obtained a crude 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine.

[0019] Next, the crude 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine is crystalized with methanol to obtain a crystalized 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine. Next, the crystalized 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine is purified with column by 9:1 of hexane and ethyl acetate to obtain a purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine.

[0020] Next, 4-nitrophenyl (thiazol-5-ylmethyl) carbonate is added to a tert-butyl ((2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenyl hexan-2-yl)carbamate in acetate medium at a temperature 68⁰C to obtain tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate.

[0021] Next, the tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate is crystalized with water to obtain a crystalized tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate. Later, the crystalized tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate is purified with column by 9.5:0.5 of hexane and ethyl acetate to obtain a purified tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S) -3-hydroxy-1,6-diphenylhexane-2,5- diyl) dicarbamate.

[0022] Next, the tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl) dicarbamate is added to HCL solution in ethyl acetate medium at a temperature 55⁰C to obtain thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate. Later, the thiazol-5-ylmethyl ((2S,3S.5S) -5- amino -3- hydroxyl -1,6- diphenylhexan-2- yl) carbamate is filtered to obtained a crude thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate.

[0023] Next, the thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate is crystalized with water to obtain a crystalized thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate. Later, the crystalized thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate is purified with column by 9:1 of hexane and ethyl acetate to obtain a purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate.

[0024] Next, the purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate is added to the purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine in methanol solution at a temperature to obtain the formula (XI). Later, the formula (XI) is filtered to obtain a crude formula (XI).

[0025] Later, the crude formula (XI) is crystalized with methanol to obtain a crystalized formula (XI). Next, the crystalized formula (XI) is purified with column by 5:5 of hexane and ethyl acetate to obtain the purified formula (XI).

[0026] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed description of drawings:
[0027] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an embodiment of the invention, and, together with the description, explain the principles of the invention.

[0028] FIG. 1 illustrates an exemplary flowchart of a preparation method for a formula (IX), in accordance to an exemplary embodiment of the invention.

[0029] FIG. 2 illustrates an exemplary flowchart of a preparation method for a purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV), in accordance to an exemplary embodiment of the invention.

[0030] FIG. 3 illustrates an exemplary flowchart of a preparation method for a purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII), in accordance to an exemplary embodiment of the invention.
Detailed invention disclosure:
[0031] Various embodiments of the present invention will be described in reference to the accompanying drawings. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps.

[0032] The present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a compound and a method of preparing the compound in connection with individuals infected with human immunodeficiency virus (HIV).

[0033] According to an exemplary embodiment of the invention, a formula (IX) for antiretroviral therapy (ART). The formula (IX) is thiazol-5-ylmethyl ((2S,3S,5S) -5- ((((1S,4R) -4- (2-amino-6-(cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1-yl) methyl) amino) -3-hydroxy-1,6- diphenylhexan-2-ylcarbamate.
Formula (IX)

[0034] According to another exemplary embodiment of the invention, FIG. 1 refers to an exemplary flowchart of a preparation method 100 for a formula (IX). At step 102, a purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII) is added to a purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV) in methanol solution at a temperature to obtain the formula (XI), as depicted in scheme VI.

[0035] Scheme VI:

[0036] At step 104, the formula (XI) is filtered to obtain a crude formula (XI). At step 106, the crude formula (XI) is crystalized with methanol to obtain a crystalized formula (XI). At step 108, the crystalized formula (XI) is purified with column by 5:5 of hexane and ethyl acetate to obtain the purified formula (XI).

[0037] According to another exemplary embodiment of the invention, FIG. 2 refers to an exemplary flowchart of a preparation method 200 for the purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV). At step 202, N- (2-amino-4-chloro-6- (((1R,4S) -4- (hydroxymethyl) cyclopent-2-en-1- yl) amino) pyrimidin-5-yl) formamide of formula (I) is added to triethyl ortho formate in an ethanol and HCl medium to obtain ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II).

[0038] Scheme I:

[0039] At step 204, the ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II) is filtered to obtained a crude ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II).

[0040] At step 206, the crude ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II) is crystalized at pH 7 with 10% NaHCO3 solution to obtain a crystalized ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II).

[0041] At step 208, the crystalized ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II) is purified with column by 9:1 of hexane and ethyl acetate to obtain a purified ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II).

[0042] At step 210, the purified ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol of formula (II) is added to cyclopropyl amine in isopropyl alcohol(IPA) medium in presence of NaHCO3 at a temperature 82⁰C to obtain ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol of formula (III). At step 212, ((1S,4R) -4- (2-amino-6-(cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol of formula (III) is filtered to obtained a crude ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol of formula (III).

[0043] Scheme II:

[0044] At step 214, the crude ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol of formula (III) is crystalized with isopropanol (IPA) solution to obtain a crystalized ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol of formula (III).

[0045] At step 216, the crystalized ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl)cyclopent-2-en-1- yl) methanol of formula (III) is purified with column by 6:4 of hexane and ethyl acetate to obtain a purified ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol of formula (III).

[0046] At step 218, the purified ((1S,4R) -4- (2-amino-6- (cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol of formula (III) is added to SOCl2 in isopropyl alcohol(IPA) medium in presence of dimethyl formamide (DMF) in dichloro methane (DCM) medium at a temperature 200C to obtain 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV).

[0047] Scheme IV:

[0048] At step 220, the 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV) is filtered to obtained a crude 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV).

[0049] At step 222, the crude 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV) is crystalized with methanol to obtain a crystalized 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV).

[0050] At step 224, the crystalized 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV) is purified with column by 9:1 of hexane and ethyl acetate to obtain the purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine of formula (IV).

[0051] According to another exemplary embodiment of the invention, FIG. 3 refers to an exemplary flowchart of a preparation method 300 for the purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII). At step 302, 4-nitrophenyl (thiazol-5-ylmethyl) carbonate of formula (V) is added to a tert-butyl ((2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenyl hexan-2-yl)carbamate of formula (VI) in acetate medium at a temperature 68⁰C to obtain tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate of formula (VII).

[0052] Scheme V:

[0053] At step 304, the tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate of formula (VII) is crystalized with water to obtain a crystalized tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate of formula (VII).

[0054] At step 306, the crystalized tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl)dicarbamate of formula (VII) is purified with column by 9.5:0.5 of hexane and ethyl acetate to obtain a purified tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S) -3-hydroxy-1,6-diphenylhexane-2,5- diyl) dicarbamate of formula (VII).

[0055] At step 308, the purified tert-butyl (thiazol-5-ylmethyl) ((2S,3S,5S)-3-hydroxy-1,6-diphenylhexane-2,5- diyl) dicarbamate of formula (VII) is added to HCL solution in ethyl acetate medium at a temperature 55⁰C to obtain thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII).

[0056] At step 310, the thiazol-5-ylmethyl ((2S,3S.5S) -5- amino -3- hydroxyl -1,6- diphenylhexan-2- yl) carbamate of formula (VIII) is filtered to obtained a crude thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII).

[0057] At step 312, the thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII) is crystalized with water to obtain a crystalized thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII). At step 138, the crystalized thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII) is purified with column by 9:1 of hexane and ethyl acetate to obtain the purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate of formula (VIII).

[0058] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure, a compound and a method of preparing the compound in connection with individuals infected with human immunodeficiency virus (HIV).

[0059] The proposed composition for antiretroviral therapy (ART) drug exhibits the characteristics of nucleoside reverse transcriptase inhibitors (NRTI) and protases inhibitor(PI). The method for synthesis of antiretroviral therapy (ART) drug can be used to control HIV with both NRTI and PI activity.

[0060] It will readily be apparent that numerous modifications and alterations can be made to the processes described in the foregoing examples without departing from the principles underlying the invention, and all such modifications and alterations are intended to be embraced by this application.
, Claims:CLAIMS:
We Claim:
1. A formula (IX) for antiretroviral therapy (ART), comprising:
(IX)

Wherein, the formula (IX) is thiazol-5-ylmethyl ((2S,3S,5S)-5-((((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1-yl)methyl)amino)-3-hydroxy-1,6- diphenylhexan-2-ylcarbamate.
2. A preparation method for a formula (IX), comprising:
adding a purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate to a purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine in methanol solution at a temperature to obtain the formula (XI), and filtering the formula (XI) to obtained a crude formula (XI), and
crystalizing the crude formula (XI) with methanol to obtain a crystalized formula (XI), thereby purifying the crystalized formula (XI) with column by 5:5 of hexane and ethyl acetate to obtain a purified formula (XI).
3. The preparation method for a formula (IX) as claimed in claim 2, wherein a method for preparation of the purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine, comprising:
adding N- (2-amino-4-chloro-6- (((1R,4S) -4- (hydroxymethyl) cyclopent-2-en-1- yl) amino) pyrimidin-5-yl) formamide to triethyl ortho formate in an ethanol and HCl medium to obtain ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol, and filtering the ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol to obtained a crude ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol;
crystalizing the crude ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol at pH 7 with 10% NaHCO3 solution to obtain a crystalized ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol, thereby purifying the crystalized ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol with column by 9:1 of hexane and ethyl acetate to obtain a purified ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol;
adding the purified ((1S,4R) -4- (2-amino-6-chloro-9H-purin- 9-yl) cyclopent-2-en-1-yl) methanol to cyclopropyl amine in isopropyl alcohol(IPA) medium in presence of NaHCO3 at a temperature 82⁰C to obtain ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol, and filtering the ((1S,4R) -4- (2-amino-6-(cyclopropylamino) -9H-purin-9-yl) cyclopent-2-en-1- yl) methanol to obtained a crude ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol;
crystalizing the crude ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol with isopropanol (IPA) solution to obtain a crystalized ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol, thereby purifying the crystalized ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol with column by 6:4 of hexane and ethyl acetate to obtain a purified ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol;
adding the purified ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol to SOCl2 in isopropyl alcohol(IPA) medium in presence of dimethyl formamide (DMF) in dichloro methane (DCM) medium at a temperature 200C to obtain 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine, and filtering the 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine to obtained a crude 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine, and
crystalizing the crude 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine with methanol to obtain a crystalized 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine, thereby purifying the crystalized 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine with column by 9:1 of hexane and ethyl acetate to obtain a purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine.
4. The preparation method for a formula (IX) as claimed in claim 3, wherein a reaction condition for the purified ((1S,4R)-4-(2-amino-6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-2-en-1- yl)methanol to mix with SOCl2 in isopropyl alcohol(IPA) medium is maintained at temperature range of 15-30° C.
5. The preparation method for a formula (IX) as claimed in claim 3, wherein a condensation reaction of the purified 9- ((1R,4S) -4- (chloromethyl) cyclopent-2-en-1-yl) -N-cyclopropyl-9H-purine-2,6-diamine with the purified thiazol-5-ylmethyl ((2S,3S.5S) -5-amino-3-hydroxy-1,6-diphenylhexan-2- yl) carbamate is performed at a temperature range of 20-50° C.