Vorinostat (Zolinza)

Vorinostat, MK0683

CAS 149647-78-9

Zolinza, SAHA, suberoylanilide hydroxamic acid, Suberanilohydroxamic acid, N-hydroxy-N'-phenyloctanediamide

US patent 5369108, PDT PATENT

For the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. Inhibits histone deacetylase I & 3.

• CCRIS 8456
• HSDB 7930
• M344
• N-Hydroxy-N'-phenyloctanediamide
• SAHA
• SAHA cpd
• Suberanilohydroxamic acid
• suberoylanilide hydroxamic acid
• UNII-58IFB293JI
• MK0683

Average: 264.3202 Monoisotopic: 264.147392516
Chemical Formula	C14H20N2O3

N-hydroxy-N'-phenyl-octanediamide
Trade names	Zolinza, 100 MG, CAPSULE, ORAL
	ZOLINZA (VORINOSTAT) [Merck Sharp & Dohme Corp.]
MedlinePlus	a607050
Licence data	US FDA:link
	LAUNCHED 2006 MERCKhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021991s002lbl.pdf
Legal status	℞-only (US)
Routes	Oral
Pharmacokinetic data
Protein binding	71%
Metabolism	Hepatic glucuronidation andoxidation CYP system not involved
Half-life	2 hours
Excretion	Renal (negligible)
Identifiers
CAS number	149647-78-9
ATC code	L01XX38
Chemical data
Formula	C14H20N2O3
Mol. mass	264.32 g/mol

CLINICAL TRIALS..http://clinicaltrials.gov/search/intervention=Vorinostat

Vorinostat (rINN) also known as suberanilohydroxamic acid (suberoyl+anilide+hydroxamic acid abbreviated as SAHA) is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.

Vorinostat is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after treatment with other medicines.^[1] The compound was developed by Columbia University chemist, Ronald Breslow.

VORINOSTAT

Vorinostat was the first histone deacetylase inhibitor^[2] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006. It is manufactured by Patheon, Inc., in Mississauga, Ontario, Canada, for Merck & Co., Inc., White House Station, New Jersey.^[3]

ZOLINZA contains vorinostat, which is described chemically as N-hydroxy-N'-phenyloctanediamide. The empirical formula is C₁₄H₂₀N₂O₃. The molecular weight is 264.32 and the structural formula is:

Vorinostat is a white to light orange powder. It is very slightly soluble in water, slightly soluble in ethanol, isopropanol and acetone, freely soluble in dimethyl sulfoxide and insoluble in methylene chloride. It has no chiral centers and is non-hygroscopic. The differential scanning calorimetry ranged from 161.7 (endotherm) to 163.9°C. The pH of saturated water solutions of vorinostat drug substance was 6.6. The pKa of vorinostat was determined to be 9.2.

Each 100 mg ZOLINZA capsule for oral administration contains 100 mg vorinostat and the following inactive ingredients: microcrystalline cellulose, sodium croscarmellose and magnesium stearate. The capsule shell excipients are titanium dioxide, gelatin and sodium lauryl sulfate.

Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for Zinc ions also found in the active site of histone deacetylases ^[4] Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation. ^[4]
SAHA inhibits class I and class II HDACs at nanomolar concentrations and arrests cell growth in a wide variety of transformed cells in culture at 2.5-5.0 µM. This compound efficiently suppressed MES-SA cell growth at a low dosage (3 µM) already after 24 hours treatment. Decrease of cell survival was even more pronounced after prolonged treatment and reached 9% and 2% after 48 and 72 hours of treatment, respectively. Colony forming capability of MES-SA cells treated with 3 µM vorinostat for 24 and 48 hours was significantly diminished and blocked after 72 hours.

Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.^[5]

A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4 - 4.4 months in earlier studies).^[6] Further brain tumor trials are planned in which vorinostat will be combined with other drugs.

Including vorinostat in treatment of advanced non-small-cell lung cancer (NSCLC) showed improved response rates and increased median progression free survival and overall survival (although the survival improvements were not significant at the P=0.05 level).^[7]

It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with Idarubicin and Cytarabine.^[8]

 

Vorinostat is an interesting target for scientists interested in eradicating HIV from infected persons.^[9] Vorinostat was recently shown to have both in vitro and in vivo effects against latently HIV infected T-cells.^[10][11]

Vorinostat, represented by structural formula (I) and chemically named as N-hydroxy-N'- phenyl-octanediamide or suberoylanilide hydroxamic acid (SAElA), is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities and vorinostat is marketed, under the brand name Zolinza^®, for the treatment of a type of skin cancer called cutaneous T-cell lymphoma (CTCL). Vorinostat is approved to be used when the disease persists, gets worse, or comes back during or after treatment with other medicines. Vorinostat has also been used to treat Sέzary's disease and, in addition, possesses some activity against recurrent glioblastoma multiforme.

Vorinostat was first described in US patent 5369108, wherein four different synthetic routes for the preparation of vorinostat are disclosed (Schemes 1 to 4).

The single step process illustrated in Scheme 1 involves coupling of the diacid chloride of suberic acid with aniline and hydiOxylamine hydrochloride. However, the yield of this reaction is only 15-30%.

Scheme 1

The multistep process illustrated in Scheme 2 begins with the monomethyl ester of suberic acid, which undergoes conversion to the corresponding acid chloride. Further coupling with aniline gives the methyl ester of suberanilic acid. Hydrolysis of the ester and further coupling with benzyl protected hydroxylamine gives benzyl protected vorinostat which on deprotection gives vorinostat.

HO. (CH₂J₆ OMe . ,OOMM e

O O

Scheme 2

In addition to the disadvantage of being a five-step process with overall yields reported as 35-65%, this process suffers from further disadvantages such as the use of the expensive monomethyl ester of suberic acid.

Scheme 3

The two step process illustrated in Scheme 3 involves coupling of the diacid chloride of suberic acid with aniline and O-benzyl hydroxylamine and then deprotection. However, the overall yield of this reaction is only 20-35%.

Scheme 4

The process illustrated in Scheme 4 is similar to that illustrated in Scheme 3, with the exception that O-trimethylsilyl hydroxylamine was used instead of O-benzyl hydroxylamine. The overall yield of this reaction is reported as 20-33%.

Another process for the preparation of vorinostat has been reported in J. Med. Chem.,

1995, vol. 38(8), pages 1411-1413. The reported process, illustrated in Scheme 5, begins with the conversion of suberic acid to suberanilic acid by a high temperature melt reaction.

Suberanilic acid is further converted to the corresponding methyl ester using Dowex resin and the methyl ester of suberanilic acid thus formed is converted to vorinostat by treatment with hydroxylamine hydrochloride. However, this process employs high temperatures (190⁰C) in the preparation of vorinostat which adds to the inefficiency and high processing costs on commercial scale. The high temperatures also increase the likelihood of impurities being formed during manufacture and safety concerns. The overall yield reported was a poor 35%.

MeOH, Dowex, 22 hours

Scheme 5

Another process for the preparation of vorinostat has been reported in OPPI Briefs, 2001, vol. 33(4), pages 391-394. The reported process, illustrated in Scheme 6, involves conversion of suberic acid to suberic anhydride, which on treatment with aniline gives suberanilic acid. Coupling of this suberanilic acid with ethyl chloroformate gives a mixed anhydride which upon treatment with hydroxylamine gives vorinostat in an overall yield of 58%. In the first step, there is competition between the formation of suberic anhydride and the linear anhydride and consequently isolation of pure suberic anhydride from the reaction mixture is very difficult. This process step is also hindered by the formation of process impurities and competitive reactions. In the second step, there is formation of dianilide by reaction of two moles of aniline with the linear anhydride. In the third step, suberanilic acid is an inconvenient by-product as the suberanilic acid is converted to a mixed anhydride with ethyl chloroformate, which is highly unstable and is converted back into suberanilic acid. Consequently, it is very difficult to obtain pure vorinostat from the reaction mixture. Although the reported yield was claimed to be 58%, when repeated a yield of only 38% was obtained.

Scheme 6

A further process for the preparation of vorinostat has been reported in J. Med. Chem., 2005, vol. 48(15), pages 5047-5051. The reported process, illustrated in Scheme 7, involves conversion of monomethyl suberate to monomethyl suberanilic acid, followed by coupling with hydroxylamine hydrochloride to afford vorinostat in an overall yield of 79%. However, the process uses the expensive monomethyl ester of suberic acid as starting material.

HOBt, DCC, DMF, RT, 4 hours

Processes for the preparation of vorinostat, and its form 1 crystalline polymorph, have been disclosed in patent applications US 2004/0122101 and WO 2006/127319. However, the disclosed processes, comprising the preparation of vorinostat from suberic acid, are a cumbersome three step process comprising the sequential steps of amidation of suberic acid with aniline, esterification of the mono-amide product with methanol, and finally reaction with hydroxylamine hydrochloride and sodium methoxide to afford vorinostat. This process is not very convenient as it involves elevated temperatures, lengthy reaction times and has a low overall yield of around 23%. In addition, the intermediate products and final product are not very pure and require exhaustive purification steps.

CLIP

Vorinostat (ZolinzaTM) Vorinostat, a histone deacetylase (HDAC) inhibitor from Merck, was approved for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma.

Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3 and HDAC6 at nanomolar concentrations. HDAC inhibitors are potent differentiating agents toward a variety of neoplasms, including leukemia and breast and prostate cancers [58].

Commercially available monomethyl ester 125 wasVorinostat (ZolinzaTM) Vorinostat, a histone deacetylase (HDAC) inhibitor from Merck, was approved for the treatment of cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin’s lymphoma.

Vorinostat was shown to inhibit HDAC1, HDAC2, HDAC3 and HDAC6 at nanomolar concentrations. HDAC inhibitors are potent differentiating agents toward a variety of neoplasms, including leukemia and breast and prostate cancers [58].

Commercially available monomethyl ester 125 was reacted with aniline in the presence of DCC and HOBt in DMF to give amide 127 in 89%yield [59] (Scheme 16).

Methyl ester amide 127 was then reacted with hydroxylamine HCl salt and potassium hydroxide in methanol to give vorinostat(XVI) in 90% yield.

[58] Breslow, R.; Marks, P.A.; Rifkind, R. A.; Jursic, B. WO9307148,2003.
[59] Gediya, L. K.; Chopra, P.; Purushottamachar, P.; Maheshwari, N.;Njar, V. C. O. J. Med. Chem., 2005, 48, 5047.

PATENT

VORINOSTAT

http://www.google.com/patents/EP2349985A2

A preferred embodiment of the first aspect of the present invention is illustrated in Scheme

suberic acid subefanilic acid      NH₂OHHCl, CDI

suberoylanilide hydroxamic acid (T)

Scheme 8

Optionally, an activating agent can be used in step (a) and/ or step (b) to afford products with high yields and purity. Preferably, the activating agent is selected from cyanuric chloride, cyanuric fluoride, catecholborane, or a mixture thereof. The activating agent is preferably used in combination with the coupling agent. A preferred embodiment of the process according to the first aspect of the present invention comprises the following steps:

(i) taking a mixture of THF, CDI and DCC;

(ii) adding suberic acid; (iii) adding aniline in THF to the solution from step (ii);

(iv) stirring at 25-30°C;

(v) filtering off the solid dicyclohexyl urea formed in the reaction;

(vi) concentrating the filtrate in vacuo;

(vii) adding a solution of KOH in water; (vϋi) filtering off the solid by-product;

(ix) heating the filtrate;

(x) adding aq. HCl;

(xi) isolating suberanilic acid;

(xii) mixing the suberanilic acid and CDI in DMF; (xiii) adding hydroxylamine hydrochloride as solid to the mixture from step (xii);

(xiv) isolating vorinostat from the mixture obtained in step (xiii);

(xv) adding acetonitrile and aq. ammonia to the vorinostat from step (xiv);

(xvi) heating the mixture;

(xvii) cooling the mixture to 20-27°C; and (xvϋi) isolating pure vorinostat from the mixture obtained in step (xvii).

Preferably, by utilising the same organic solvent in steps (a) and (b), pure vorinostat can be obtained without isolation of any synthetic intermediate^).

A preferred embodiment of the second aspect of the present invention is illustrated in Scheme 9.

suberic acid N-hydtoxy-7-carboxy-heptanamide

Example 1

Stage 1 : Conversion of suberic acid to suberanilic acid

A mixture of CDI (0.5eq) and DCC (0.8eq) in THF (15 vol) was stirred for 1 hour at 25- 3O⁰C. Suberic acid (leq) and aniline (leq) in THF (1 vol) was added and the mixture stirred for a further 16-20 hours. The solid by-product was removed by filtration and the filtrate was concentrated in vacuo at 5O⁰C. The solid residue obtained was treated with a solution of KOH (2eq) in water (10 vol) and stirred for 30 minutes at 25-30⁰C and any solid byproduct formed was removed by filtration. The filtrate obtained was heated at 6O⁰C for 3-4 hours and cooled to 20⁰C before addition of an aqueous solution of HCl (17.5%, 3 vol). The mixture was stirred for 30 minutes and the solid filtered, washed with water (2x5 vol) and dried under vacuum at 60-65⁰C. Molar Yield = 60-65% Purity by HPLC = 99.5%

Stage 2: Conversion of suberanilic acid to crude vorinostat The suberanilic acid (leq) obtained in stage 1 was dissolved in DMF (5 vol) and CDI (2eq) was added at 25-3O⁰C and maintained for 30 minutes under stirring. Hydroxylamine hydrochloride (4eq) was added and stirring continued for 30 minutes. Water (25 vol) was then added and the mixture stirred for 2 hours. The precipitated solid was filtered, washed with water (2x5 vol) and dried under vacuum at 50⁰C. Molar Yield = 70-75% Purity by HPLC = 99% Stage 3: Purification of crude vorinostat

Aqueous ammonia (2.5 vol) was added to the crude vorinostat (leq) in acetonitrile (15 vol) at 25-30°C. The mixture was then maintained at 55-60°C for 1 hour before being cooled to 20-25°C and being stirred for a further hour. The resulting solid was filtered, washed with acetonitrile (2x0.5 vol) and dried under vacuum at 45-5O⁰C for 5 hours. Molar Yield = 55-60% Purity by HPLC > 99.8%

Example 2

Stage 1 : Conversion of suberic acid to crude vorinostat

A mixture of CDI (0.5eq) and DCC (0.8eq) in THF (15 vol) was stirred for 1 hour at 25- 30°C. Suberic acid (leq) and hydroxylamine (leq) in THF (1 vol) was added and the mixture stirred for a further 1 hour. Then CDI (0.5eq), DCC (0.8eq) and aniline (leq) were added to the mixture and the mixture was stirred for a further 16-20 hours. The solid byproduct was removed by filtration and the filtrate was concentrated in vacuo at 50°C to obtain crude vorinostat. Molar Yield = 55-60% Purity by HPLC > 95.8%

Stage 2: Purification of crude vorinostat

Aqueous ammonia (2.5 vol) was added to the crude vorinostat (leq) in acetonitrile (15 vol) at 25-3O⁰C. The mixture was then maintained at 55-60⁰C for 1 hour before being cooled to 20-25⁰C and being stirred for a further hour. The resulting solid was filtered, washed with acetonitrile (2x0.5 vol) and dried under vacuum at 45-50⁰C for 5 hours. Molar Yield = 35-40% Purity by HPLC > 99.8%

PATENT

SYNTHESIS

WO2009098515A1

Scheme V. - -

Vorinostat
Suberic acid (l.Oeq) was dissolved in tetrahydrofuran (15vol) and the clear solution was chilled to 0-5°C. Methyl chloro formate (l.leq) and triethylamine (1.1 eq) were added to the solution at the same temperature and the mixture was stirred for 15 minutes. The triethylamine.HCl salt formed was filtered off, then aniline (leq) was added to the reaction mixture at 0-5⁰C and stirring was continued for 15 minutes. Methyl chloroformate (l.leq) and triethylamine (l.leq) were added to the clear solution and stirring was continued for a further 15 minutes at 0-5°C. This chilled reaction mixture was added to a freshly prepared hydroxylamine solution in methanol (*see below) chilled to 0-5°C and stirred for 15 minutes at 0-5°C. The solvent was removed under vacuum at 40°C and the residue obtained was taken in methylene dichloride and the organic solution was washed with water and dried over anhydrous sodium sulfate. Methylene dichloride was removed under vacuum at 40°C and acetonitrile was added to the residue. This mixture was stirred for 15 minutes before the solid was filtered under vacuum and dried under vacuum at 60°C to afford the product as a white solid. Molar yield = 35-41%; HPLC purity = 99.90%.
VORINOSTAT
¹H-NMR (DMSO-d₆): 1.27 (m, 4H, 2 x -CH₂-), 1.53 (m, 4H, 2 x -CH₂-), 1.94 (t, J = 7.3 Hz, 2H, -CH₂-), 2.29 (t, J = 7.4 Hz, 2H, -CH₂-), 7.03 (t, J = 7.35 Hz, IH, aromatic para position), 7.27 (t, J = 7.90 Hz, 2H, aromatic meta position), 7.58 (t, J = 7.65 Hz, 2H, aromatic ortho position), 8.66 (s, IH, -OH, D₂O exchangeable), 9.85 (s, IH, amide -NH-, D₂O exchangeable), 10.33 (s, IH, -NH-OH, D₂O exchangeable).
¹³C-NMR (DMSO-d₆): 25.04 (2C, 2 x -CH₂-), 28.43 (2C, 2 x -CH₂-), 32.24 (1C, -CH₂-), 36.34 (1C, -CH₂-), 119.01 (2C, Ar-C), 122.96 (1C, Ar-C), 128.68 (2C, Ar-C), 139.24 (1C, Ar- C, =CNH-), 169.23 (1C, -CO-), 171.50 (1C, -CO-).
*Preparation of hydroxylamine solution:
Potassium hydroxide (l.leq) was added to methanol (8vol) and the solution was chilled to 0-5°C. Similarly hydroxylamine hydrochloride (l.leq) was added to methanol (8vol) and chilled to 0-5°C. The chilled amine solution was added to the chilled alkali solution and stirred for 15 minutes at 0-5⁰C. The white potassium chloride salt was filtered off and the filtrate was used as such.

PATENT

POLYMORPHS

US20040122101

The present invention is directed to a Form I polymorph of SAHA characterized by an X-ray diffraction pattern substantially similar to that set forth in FIG. 13A. SAHA Form I is also characterized by an X-ray diffraction pattern including characteristic peaks at about at about 9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0, and 43.3 degrees 2θ. SAHA Form I is further characterized by an X-ray diffraction pattern including characteristic peaks at about 9.0, 9.4, 17.5, 19.4, 20.0, 24.0, 24.4, 24.8, 25.0, 28.0, 43.3 degrees 20, and lacking at least one peak at about <8.7, 10.0-10.2, 13.4-14.0, 15.0-15.2, 17.5-19.0, 20.1-20.3, 21.1-21.3, 22.0-22.22, 22.7-23.0, 25.0-25.5, 26.0-26.2, and 27.4-27.6 degrees 2θ.

PAPER

SPECTRAL DATA AND SYNTHESIS
Journal of Medicinal Chemistry, 2011 ,  vol. 54,  13  pg. 4694 - 4720
http://pubs.acs.org/doi/full/10.1021/jm2003552
 http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf
for structures see above link
Suberoylanilide hydroxamic acid (26, SAHA, vorinostat).
Suberic acid monomethyl ester (23) (15.09 g, 80.2 mmol) and DMF (0.10 mL) in anhydrous
DCM (300 mL) was added SOCl2 (34.6 mL, 0.481 mol), and the reaction mixture was refluxed for 3
h. The mixture was then concentrated. Toluene (300 mL) was added to the residue and evaporated
to afford crude acid chloride 24. Crude 24 was dissolved in DCM (240 mL), and followed by
addition of aniline (7.3 mL, 80.2 mmol) and Et3N (16.9 mL, 0.120 mol). The reaction mixture was
stirred for 90 min at room temp. The course of reaction was monitored by TLC (30% EtOAc in
hexanes) and LC–MS. DCM was removed, and ethyl acetate (500 mL) was added to dissolve the
residue. The organic layer was washed with aqueous NaHCO3 (500 mL × 2), 1 N HCl (400 mL × 2),
water, dried (Na2SO4), and evaporated to dryness under reduced pressure. The residue was purified
by vacuum liquid chromatography (silica, 20% EtOAc in hexanes) to afford compound 25as white crystalline solids (20.15 g, 96 %). NaOMe in MeOH solution (5.4 M, 106 mL, 0.573 mol) was added to a solution of compound 25 (10.05 g, 38.2 mmol) and NH2OH·HCl (26.54 g, 0.382 mol) in
dry MeOH (375 mL). The reaction mixture was stirred for 40 min at room temp. The reaction was
quenched by adding of 1 N HCl to pH 7–8. MeOH was removed under reduced pressure and water
(1 L) was added to the residue. The precipitated solid was filtered and washed with water (300 mL)
and EtOAc (150 mL) to afford crude 26 which was further purified by recrystallization. MeOH (200
mL) was added to crude 26 (5 g) and warmed to dissolve all solids. The MeOH solution was filtered,
and deionized water (400 mL) was added to the filtrate, the resulting solution was placed at 4 oC
overnight. Crystals obtained were filtered and washed with deionized water (100 mL) to afford pure
26 (vorinostat, SAHA) as off-white crystals. Overall yield: 80–85% from compound 23. Compound
26,
LC–MS m/z 265.1 ([M + H]+).

1H NMR (DMSO-d6)  10.35 (1H, s), 9.86 (1H, s), 8.68 (1H, s),
7.58 (2H, d, J = 7.6 Hz), 7.28 (2H, t, J = 7.5 Hz), 7.02 (1H, t, J = 7.4 Hz), 2.29 (2H, t, J = 7.4 Hz),
1.94 (2H, t, J = 7.4 Hz), 1.57 (2H, m), 1.49 (2H, m), 1.33 - 1.20 (2H, m); 13C NMR (DMSO-d6) 
171.2, 169.1, 139.3, 128.6, 122.9, 119.0, 36.3, 32.2, 28.4, 28.3, 25.0. Anal. (C10H20N2O3) C, H, N.
CLIP

Suberic acid monomethyl ester (23) (15.09 g, 80.2 mmol) and DMF (0.10 mL) in anhydrous DCM (300 mL) was added SOCl2 (34.6 mL, 0.481 mol), and the reaction mixture was refluxed for 3 h. The mixture was then concentrated. Toluene (300 mL) was added to the residue and evaporated to afford crude acid chloride 24. Crude 24 was dissolved in DCM (240 mL), and followed by addition of aniline (7.3 mL, 80.2 mmol) and Et3N (16.9 mL, 0.120 mol). The reaction mixture was stirred for 90 min at room temp. The course of reaction was monitored by TLC (30% EtOAc in hexanes) and LC–MS. DCM was removed, and ethyl acetate (500 mL) was added to dissolve the residue. The organic layer was washed with aqueous NaHCO3 (500 mL × 2), 1 N HCl (400 mL ×2), water, dried (Na2SO4), and evaporated to dryness under reduced pressure. The residue was purified by vacuum liquid chromatography (silica, 20% EtOAc in hexanes) to afford compound 25 as white crystalline solids (20.15 g, 96 %). NaOMe in MeOH solution (5.4 M, 106 mL, 0.573 mol) was added to a solution of compound 25 (10.05 g, 38.2 mmol) and NH2OH·HCl (26.54 g, 0.382 mol) in dry MeOH (375 mL). The reaction mixture was stirred for 40 min at room temp. The reaction was quenched by adding of 1 N HCl to pH 7–8. MeOH was removed under reduced pressure and water (1 L) was added to the residue. The precipitated solid was filtered and washed with water (300 mL) and EtOAc (150 mL) to afford crude 26 which was further purified by recrystallization. MeOH (200 mL) was added to crude 26 (5 g) and warmed to dissolve all solids. The MeOH solution was filtered,  S37 and deionized water (400 mL) was added to the filtrate, the resulting solution was placed at 4 oC overnight. Crystals obtained were filtered and washed with deionized water (100 mL) to afford pure 26 (vorinostat, SAHA) as off-white crystals. Overall yield: 80–85% from compound 23.
. Compound 26,
LC–MS m/z 265.1 ([M + H] + ).
1H NMR (DMSO-d6)  10.35 (1H, s), 9.86 (1H, s), 8.68 (1H, s), 7.58 (2H, d, J = 7.6 Hz), 7.28 (2H, t, J = 7.5 Hz), 7.02 (1H, t, J = 7.4 Hz), 2.29 (2H, t, J = 7.4 Hz), 1.94 (2H, t, J = 7.4 Hz), 1.57 (2H, m), 1.49 (2H, m), 1.33 - 1.20 (2H, m);
13C NMR (DMSO-d6)  171.2, 169.1, 139.3, 128.6, 122.9, 119.0, 36.3, 32.2, 28.4, 28.3, 25.0.
Anal. (C10H20N2O3) C, H, N.

 NMR

 1H NMR spectrum of C14H20N2O3 in CDCL3 at 400 MHz.

SEE http://www.abmole.com/download/vorinostat-hnmr.pdf

...................................................................

References

1.  "ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration" (Press release). Merck & Co. June 7, 2006. Retrieved 2006-10-06.
2.  HDAC Inhibitors Base (vorinostat)
3.  "FDA Approves New Drug for Skin Cancer, Zolinza" (Press release). Food and Drug Administration. October 6, 2006. Retrieved 2006-10-06.
4.  Richon, Victoria. "Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor". British Journal of Cancer. Retrieved 3 May 2012.
5.  Cuneo A, Castoldi. "Mycosis fungoides/Sezary's syndrome". Retrieved 2008-02-15.
6.  "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. Retrieved 2007-06-03.
7.  http://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html Dec 2009. URL dead Jan 2012
8.  "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)".
9.  "Study of the Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART". ClinicalTrials.gov. 2011-03-21.
10.  Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM (2009). "Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid.". AIDS Res Hum Retroviruses 25 (2): 207–12. doi:10.1089/aid.2008.0191. PMC 2853863. PMID 19239360.
11.  Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J et al. (2009). "Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells.". J Biol Chem 284 (11): 6782–9.doi:10.1074/jbc.M807898200. PMC 2652322. PMID 19136668.
12. Vorinostat bound to proteins in the PDB
13. J. Med. Chem.,1995, vol. 38(8), pages 1411-1413.
14. A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells
    J Med Chem 2005, 48(15): 5047
15. A new facile and expeditious synthesis of N-hydroxy-N'-phenyloctanediamide, a potent inducer of terminal cytodifferentiation
    Org Prep Proced Int 2001, 33(4): 391
16. US patent 5369108, PDT PATENT
17. WO2007/22408.........
18. WO 1993007148
19. CN 102344392

United States	7456219	APPROVAL    2006-11-14	EXPIRY 2026-11-14
United States	6087367	1994-10-04	2011-10-04
Canada	2120619	2006-11-21	2012-10-05

Patent	Patent Expiry	pat use code
7399787	Feb 9, 2025	U-892
7456219	Mar 11, 2027
7652069	Mar 4, 2023
7732490	Mar 4, 2023	U-892
7851509	Feb 21, 2024	U-892
8067472	Mar 4, 2023	U-892
8093295	May 16, 2026
8101663	Mar 4, 2023	U-892
RE38506	Nov 29, 2013

U 892 =TREATMENT OF CUTANEOUS MANIFESTATIONS IN PATIENTS WTIH CUTANEOUS T-CELL LYMPHOMA (CTCL)

Exclusivity Code	Exclusivity_Date
ODE	Oct 6, 2013

WO2009098515A1 *

Feb 6, 2009

Aug 13, 2009

Generics Uk Ltd

Novel process for the preparation of vorinostat

Marks, P.A., Breslow, R. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotech 25(1) 84-90 (2007). DOI: 10.1038/nbt1272
Takashi Kumagai, et al. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells. International Journal of Cancer. 2007 Aug 1;121(3):656-65. DOI: 10.1002/ijc.22558
Hrzenjak A, et al. Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo. Mol Cancer. 2010 Mar 4;9:49. DOI: 10.1186/1476-4598-9-49

...................................................................................................

Title: Vorinostat CAS Registry Number: 149647-78-9 CAS Name: N-Hydroxy-N¢-phenyloctanediamide Additional Names: suberoylanilide hydroxamic acid; SAHA Molecular Formula: C14H20N2O3 Molecular Weight: 264.32 Percent Composition: C 63.62%, H 7.63%, N 10.60%, O 18.16% Literature References: Second generation hybrid polar compound; histone deacetylase (HDAC) inhibitor that induces cell cycle arrest, differentiation and apoptosis in tumor cells. Prepn: R. Breslow et al., WO 9307148; eidem, US 5369108 (1993, 1994 both to Sloan-Kettering Inst.; Columbia Univ.); J. C. Stowell et al., J. Med. Chem. 38, 1411 (1995). Synthesis: A. Mai et al., Org. Prep. Proceed. Int. 33, 391 (2001). HTLC determn in serum: L. Du et al., Rapid Commun. Mass Spectrom. 19, 1779 (2005). In vitroantiproliferative activity: P. N. Munster et al., Cancer Res. 61, 8492 (2001). In vivo antineoplastic activity: L. A. Cohen et al.,Anticancer Res. 22, 1497 (2002). Clinical pharmacokinetics and activity in cancer patients: W. K. Kelly et al., J. Clin. Oncol. 23, 3923 (2005). Review of mechanism of action: V. M. Richon et al., Blood Cells Mol. Dis. 27, 260-264 (2001); of development and therapeutic potential: R. W. Johnstone, IDrugs 7, 674-682 (2004). Properties: White solid, mp 159-160.5°. Melting point: mp 159-160.5° Therap-Cat: Antineoplastic. Keywords: Antineoplastic.

US7148257	Aug 26, 2003	Dec 12, 2006	Merck Hdac Research, Llc	Methods of treating mesothelioma with suberoylanilide hydroxamic acid
US7375137	Mar 28, 2006	May 20, 2008	Merck Hdac Research, Llc	Methods of treating cancer with HDAC inhibitors
US7399787	Jul 9, 2003	Jul 15, 2008	Merck Hdac Research, Llc	Methods of treating cancer with HDAC inhibitors
US7456219	Jun 19, 2003	Nov 25, 2008	Merck Hdac Research, Llc	Polymorphs of suberoylanilide hydroxamic acid
US7652069	Oct 30, 2007	Jan 26, 2010	Merck Hdac Research, Llc	Polymorphs of suberoylanilide hydroxamic acid
US7732490	Sep 11, 2007	Jun 8, 2010	Merck Hdac Research, Llc	Methods of treating cancer
US7847122	Mar 18, 2008	Dec 7, 2010	Merck Hdac Research, Llc	Polymorphs of suberoylanilide hydroxamic acid
US7851509	Mar 18, 2008	Dec 14, 2010	Merck Hdac Research, Llc	Polymorphs of suberoylanilide hydroxamic acid
US7879865	Nov 18, 2005	Feb 1, 2011	Sloan-Kettering Institute For Cancer Research	Treatment of cancer of the brain using histone deacetylase inhibitors
US7998957	Feb 6, 2008	Aug 16, 2011	Lixte Biotechnology, Inc.	Oxabicycloheptanes and oxabicylcoheptenes, their preparation and use
US8058268	Jul 29, 2009	Nov 15, 2011	Lixte Biotechnology, Inc.	Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
US8067472	Apr 23, 2010	Nov 29, 2011	Merck Hdac Research, Llc	Methods of treating Hodgkin's and non-Hodgkin's lymphoma
US8088951	Nov 30, 2007	Jan 3, 2012	Massachusetts Institute Of Technology	Epigenetic mechanisms re-establish access to long-term memory after neuronal loss
US8093295	May 16, 2006	Jan 10, 2012	Merck Sharp & Dohme Corp.	Formulations of suberoylanilide hydroxamic acid and methods for producing the same
US8101663	Dec 7, 2009	Jan 24, 2012	Merck Hdac Research, Llc	Polymorphs of suberoylanilide hydroxamic acid
US8143445	Oct 1, 2008	Mar 27, 2012	Lixte Biotechnology, Inc.	HDAC inhibitors
US8227473	Jul 17, 2009	Jul 24, 2012	Lixte Biotechnology, Inc.	Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US8288440 *	Jan 13, 2010	Oct 16, 2012	Merck Sharp & Dohme Corp.	Formulations of suberoylanilide hydroxamic acid and methods for producing same
US8329719	Aug 1, 2011	Dec 11, 2012	Lixte Biotechnology, Inc.	Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
US8426444	Jun 30, 2011	Apr 23, 2013	Lixte Biotechnology, Inc.	Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US8450372 *	Jan 13, 2010	May 28, 2013	Merck Sharp & Dohme Corp.	Formulations of suberoylanilide hydroxamic acid and methods for producing same
US8455688	Mar 21, 2012	Jun 4, 2013	Lixte Biotechnology, Inc.	HDAC inhibitors
US8541458	Jun 11, 2012	Sep 24, 2013	Lixte Biotechnology, Inc.	Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US8563615	Nov 1, 2010	Oct 22, 2013	Massachusetts Institute Of Technology	Use of CI-994 and dinaline for the treatment of memory/cognition and anxiety disorders
US20100112046 *	Jan 13, 2010	May 6, 2010	Jeannie Chow Wong	Formulations of suberoylanilide hydroxamic acid and methods for producing same
US20100113829 *	Jan 13, 2010	May 6, 2010	Cote Aaron S	Formulations of suberoylanilide hydroxamic acid and methods for producing same
US20100119596 *	Jan 13, 2010	May 13, 2010	Jeannie Chow Wong	Formulations of suberoylanilide hydroxamic acid and methods for producing same
US20110263712 *	Oct 14, 2009	Oct 27, 2011	Generics (Uk) Limited	Process for the preparation of vorinostat
US20110313044 *	Jun 16, 2011	Dec 22, 2011	Urquima S.A.	Polymorphs of Suberoylanilide Hydroxamic Acid
EP2079304A1 *	Sep 24, 2007	Jul 22, 2009	Merck & Co., Inc.	Amine base salts of saha and polymorphs thereof
EP2229941A1 *	May 16, 2006	Sep 22, 2010	Merck Sharp & Dohme Corp.	Formulations of suberoylanilide hydroxamic acid and methods for producing same
EP2292221A2 *	May 16, 2006	Mar 9, 2011	Merck Sharp & Dohme Corp.	Formulations of suberoylanilide hydroxamic acid and methods for producing same
WO2006127319A2 *	May 16, 2006	Nov 30, 2006	Merck & Co Inc	Formulations of suberoylanilide hydroxamic acid and methods for producing same
WO2006127321A2 *	May 16, 2006	Nov 30, 2006	Merck & Co Inc	Formulations of suberoylanilide hydroxamic acid and methods for producing same
WO2008039421A2 *	Sep 24, 2007	Apr 3, 2008	Arlene E Mckeown	Pharmaceutical compositions of hdac inhibitors and chelatable metal compounds, and metal-hdac inhibitor chelate complexes
WO2008042146A1 *	Sep 24, 2007	Apr 10, 2008	Arlene E Mckeown	Amine base salts of saha and polymorphs thereof
WO2008097654A1 *	Feb 8, 2008	Aug 14, 2008	Nancie M Archin	Methods of using saha for treating hiv infection
WO2009020565A1 *	Aug 1, 2008	Feb 12, 2009	Lixte Biotechnology Inc	Use of phosphatases to treat neuroblastomas and medulloblastomas
WO2010061220A2 *	Nov 25, 2009	Jun 3, 2010	Generics [Uk] Limited	Novel processes and pure polymorphs

EXTRAS

MS-275 (Entinostat); CI-994 (Tacedinaline); BML-210; M344; MGCD0103 (Mocetinostat); PXD101 (Belinostat); LBH-589 (Panobinostat); Tubastatin A; Scriptaid; NSC 3852; NCH 51; HNHA; BML-281; CBHA; Salermide; Pimelic Diphenylamide; ITF2357 (Givinostat); PCI-24781; APHA Compound 8; Droxinostat; SB939.

SEE COMPILATION ON SIMILAR COMPOUNDS AT ..............http://drugsynthesisint.blogspot.in/p/nostat-series.html

//////////////149647-78-9, MK0683, VORINOSTAT, Zolinza

ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1

///////