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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Coblopasvir


img

Coblopasvir.png

Coblopasvir
CAS: 1312608-46-0
Chemical Formula: C41H50N8O8
Molecular Weight: 782.89

UNII-67XWL3R65W

methyl {(2S)-1-[(2S)-2-(4-{4-[7-(2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl)-2H-1,3-benzodioxol-4-yl]phenyl}-1Himidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Carbamic acid, N-((1S)-1-(((2S)-2-(5-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methyl-1-oxobutyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-1,3-benzodioxol-4-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-, methyl ester

hepatitis C virus infection

KW-136

Coblopasvir is an antiviral drug candidate.

Coblopasvir dihydrochloride

CAS 1966138-53-3

C41 H50 N8 O8 . 2 Cl H
 Molecular Weight 855.806
PHASE 3 Beijing Kawin Technology Share-Holding
Hepatitis C virus (HCV), or hepatitis C virus infection, is a chronic blood-borne infection. Studies have shown that 40% of chronic liver diseases are associated with HCV infection, and an estimated 8,000-10,000 people die each year. HCV-related end-stage liver disease is the most common indication for liver transplantation in adults.
In the past ten years, antiviral therapy for chronic liver disease has developed rapidly, and significant improvement has been seen in the treatment effect. However, even with the combination therapy with pegylated IFN-α plus ribavirin, 40% to 50% of patients fail to treat, that is, they are non-responders or relapsers. These patients do not currently have an effective treatment alternative. Because the risk of HCV-related chronic liver disease is related to the duration of HCV infection, and the risk of cirrhosis increases in patients who have been infected for more than 20 years, chronic liver disease often progresses to advanced stages with cirrhosis, ascites, jaundice, and rupture of varicose veins. , Brain disease, and progressive liver failure, and the risk of liver cancer is also significantly increased.
HCV is a enveloped positive-strand RNA virus of the Flaviviridae family. The single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) that encodes a single open reading frame (ORF) of approximately 3,000 amino acids. Mostly polyprotein. In infected cells, cellular and viral proteases cleave this polyprotein at multiple sites to produce viral structural and non-structural (NS) proteins. There are two viral proteases that affect the production of mature non-structural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B). The first viral protease is cleaved at the NS2-NS3 junction of the polyprotein; the second viral protease is A “NS3 protease” that mediates all subsequent cleavage events at a site downstream of the NS3 position relative to the polyprotein (ie, the site between the C-terminus of NS3 and the C-terminus of the polyprotein). The NS3 protease exhibits cis-activity at the NS3-NS4 cleavage site and, conversely, exhibits trans-activity at the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is thought to provide multiple functions, such as acting as a cofactor for the NS3 protease, and may promote membrane localization of NS3 and other viral replicase components. The formation of a complex between NS3 and NS4A may be necessary for NS3-mediated processing events and improves the proteolytic efficiency at all sites recognized by NS3. NS3 protease may also exhibit nucleotide triphosphatase and RNA helicase activity. NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication. In addition, compounds that inhibit the effects of NS5A in viral replication may be useful for treating HCV.

Beijing Kawin Technology Share-Holding, in collaboration with Beijing Fu Rui Tiancheng Biotechnology and Ginkgo Pharma , is developing coblopasvir as an oral capsule formulation of dihydrochloride salt (KW-136), for treating hepatitis C virus infection. In June 2018, an NDA was filed in China by Beijing Kawin Technology and Sichuan Qingmu Pharmaceutical . In August 2018, the application was granted Priority Review in China . Also, Beijing Kawin is investigating a tablet formulation of coblopasvir dihydrochloride.

PATENT

WO2011075607 , claiming substituted heterocyclic derivatives as HCV replication inhibitors useful for treating HCV infection and liver fibrosis, assigned to Beijing Kawin Technology Share-Holding Co Ltd and InterMune Inc ,

PATENT

CN 108675998

PATENT

WO-2020001089

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020001089&tab=FULLTEXT&_cid=P22-K53D18-32430-1

Novel crystalline and amorphous forms of methyl carbamate compound, particularly coblopasvir dihydrochloride , (designated as Forms H) processes for their preparation, compositions and combinations comprising them are claimed. Also claim is an article or kit comprising a container and a package insert, wherein the container contains coblopasvir dihydrochloride.

Step 7
To a solution of compound 1-IXf (250 mg, 0.31 mmol) in toluene (10.0 mL) was added NH4OAc (4.0 g, 50 mmol) and the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed and the residue was purified by preparative HPLC to give Compound I (43.5 mg, yield 20%) as a white solid. MS (ESI) m / z (M + H) + 783.4.
Example 2 Preparation of a compound of formula II
Compound of formula (I) N-[(2S) -1-[(2S) -2- {4- [7- (4- {2-[(2S) -1-[(2S) -2-[(A Oxycarbonyl) amino] -3-methylbutanoyl] pyrrolidin-2-yl] -1H-imidazol-4-yl} phenyl) -2H-1,3-benzodioxo-4-yl] Preparation of -1H-imidazol-2-yl} pyrrolidin-1-yl] -3-methyl-1-oxobutane-2-yl] carbamate dihydrochloride
At room temperature, a solution of the pure product of structural formula I (800 g, 1.0 eq) and ethyl acetate (8 L) were sequentially added to a 20 L bottle and stirred. A 11.2% HCl / ethyl acetate solution (839 g) was added dropwise to the system, the temperature of the system was controlled at 15 ° C to 25 ° C, and the mixture was stirred for more than 3 hours to stop the reaction. The filter cake was filtered with ethyl acetate (2L). Wash the cake, bake the cake at a controlled temperature of 40-60 ° C, sample and test until the ethyl acetate residue is <0.5%, (about 73 hours of baking), to obtain the compound of formula II, off-white solid powder or granules, 774 g, HPLC Purity: 98.65%, yield: 88.5%, tested XRPD as amorphous.

///////////////Coblopasvir , KW-136, hepatitis C virus infection, CHINA, Beijing Kawin Technology, NDA, Phase III

O=C(OC)N[C@@H](C(C)C)C(N1[C@H](C2=NC(C3=CC=C(C4=C5OCOC5=C(C6=CNC([C@H]7N(C([C@@H](NC(OC)=O)C(C)C)=O)CCC7)=N6)C=C4)C=C3)=CN2)CCC1)=O

Benvitimod, Tapinarof, тапинароф , تابيناروف , 他匹那罗 ,


Chemical structure of benvitimod

ChemSpider 2D Image | 3,5-Dihydroxy-4-isopropyl-trans-stilbene | C17H18O2

Benvitimod, Tapinarof

3,5-dihydroxy-4-isopropyl-trans-stilbene

Launched – 2019 CHINA, Psoriasis, Tianji Pharma
тапинароф
 [Russian] [INN]WBI-1001

تابيناروف [Arabic] [INN]
他匹那罗 [Chinese] [INN]
(E)-2-(1-Methylethyl)-5-(2-phenylethenyl)-1,3-benzenediol
1,3-Benzenediol, 2-(1-methylethyl)-5-(2-phenylethenyl)-, (E)-
1,3-Benzenediol, 2-(1-methylethyl)-5-[(E)-2-phenylethenyl]-
10253
2-Isopropyl-5-[(E)-2-phenylvinyl]-1,3-benzenediol
3,5-Dihydroxy-4-isopropyl-trans-stilbene
5-[(E)-2-phenylethenyl]-2-(propan-2-yl)benzene-1,3-diol
79338-84-4 [RN]
84HW7D0V04
Research Code:WB-1001; WBI-1001
Trade Name:MOA:NSAID
Indication:Atopic dermatitis; PsoriasisStatus:
Phase III (Active)
Company:GlaxoSmithKline (Originator), Welichem Biotech (Originator), 天济药业 (Originator)
2894512
DMVT-505
GSK-2894512
RVT-505
WB-1001
WBI-1001
84HW7D0V04 (UNII code)
In May 2019, the drug was appoved in China for the treatment of moderate stable psoriasis vulgaris in adults and, in July 2019, Tianji Pharma (subsidiary of Guanhao Biotech) launched the product in China for the treatment of moderate stable psoriasis vulgaris in adults.

Benvitimod is in phase III clinical trials, Dermavant Sciences for the treatment of atopic dermatitis and psoriasis.

The compound was co-developed by Welichem Biotech and Stiefel Laboratories (subsidiary of GSK). However, Shenzhen Celestial Pharmaceuticals acquired the developement rights in China, Taiwan, Macao and Hong Kong.

Benvitimod (also known as Tapinarof or 3,5-dihydroxy-4-isopropyl-trans-stilbene) is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes.It is a product of an alternative ketosynthase-directed stilbenoids biosynthesis pathway. It is derived from the condensation of two β-ketoacyl thioesters. It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis.

Benvitimod (also known as tapinarof or 3,5-dihydroxy-4-isopropyl-trans-stilbene) is a bacterial stilbenoid produced in Photorhabdus bacterial symbionts of Heterorhabditis nematodes. It is a product of an alternative ketosynthase-directed stilbenoids biosynthesis pathway. It is derived from the condensation of two β-ketoacyl thioesters .[1] It is produced by the Photorhabdus luminescens bacterial symbiont species of the entomopathogenic nematode, Heterorhabditis megidis. Experiments with infected larvae of Galleria mellonella, the wax moth, support the hypothesis that the compound has antibiotic properties that help minimize competition from other microorganisms and prevents the putrefaction of the nematode-infected insect cadaver.[2]

Tapinarof is a non-steroidal anti-inflammatory drug originated by Welichem Biotech. Dermavant Sciences is developing the product outside China in phase III clinical trials for the treatment of plaque psoriasis. The company is also conducting phase II clinical trials for the treatment of atopic dermatitis. Phase II studies had also been conducted by Welichem Biotech and Stiefel (subsidiary of GlaxoSmithKline) for these indications.

Tapinarof was originated at Welichem Biotech, from which Tianji Pharma and Shenzen Celestial Pharmaceuticals obtained rights to the product in the Greater China region in 2005. In 2012, Welichem licensed development and commercialization rights in all other regions to Stiefel. In 2013, Welichem entered into an asset purchase agreement to regain Greater China rights to the product from Tianji Pharma and Celestial; however, this agreement was terminated in 2014. In 2018, Stiefel transferred its product license to Dermavant Sciences.

Entomopathogenic nematodesemerging from a wax moth cadaver

Medical research

Benvitimod is being studied in clinical trials for the treatment of plaque psoriasis.[3]

PATENTS

Route 1

1. US2003171429A1.

2. US2005059733A1.

Route 2

Reference:1. CN103265412A.

 

Patent

https://patents.google.com/patent/CN103992212A/en

phenalkenyl Maude (Benvitimod) is a new generation of anti-inflammatory drugs, are useful for treating a variety of major autoimmune diseases, such as psoriasis, eczema, hair and more concentrated colitis allergic diseases.Phenalkenyl Maud stilbene compound, comprising cis and trans isomers, the trans alkenyl benzene Maude has a strong physiological activity, stability and physical and chemical properties, and cis alkenyl benzene Modesto predominantly trans phenalkenyl Maud byproducts during synthesis, conventional methods such as benzene alkenyl Maude Wittig reaction of cis-isomer impurity is inevitable.

Figure CN103992212AD00041

[0004] benzyl trans-alkenyl Maude as main impurities in the synthesis, whether a drug is detected, or monitored during the reaction, the synthesis and analysis methods established cis alkenyl benzene Maude has very important significance.Phenalkenyl Maud conventional synthetic methods the impurity content is very low, and the properties of the cis compound is extremely unstable, easily converted to trans-structure, the synthetic method according to the preceding, the cis compound difficult to separate. The synthesis method has not been reported before in the literature. Thus, to find a synthesis route of cis-alkenyl benzene Maude critical.

[0005] The synthesis of compounds of cis-stilbene, in the prior art, there have been many reports, however, the prior art method of synthesizing a reaction product of the cis starting materials and reagents difficult source, the catalyst used is expensive higher costs, operational difficulties, is not conducive to large-scale production, such as:

① Gaukroger K, John A.Hadfield.Novel syntheses of cis and trans isomers ofcombretastatin A-4 [J] .J.0rg.Chemj 2001, (66): 8135-8138, instead of styrene and substituted phenyl bromide boric acid as the raw material, the Suzuki coupling reaction is a palladium catalyst, to give the cis compound, the reaction follows the formula:

Figure CN103992212AD00051

Yield and selectivity of the process the structure is good, but the reaction is difficult source of raw materials, catalyst more expensive, limiting the use of this method.

[0006] ② Felix N, Ngassaj Erick A, Lindsey, Brandon Ej Haines.The first Cu- and

amine-free Sonogashira-type cross-coupling in the C_6 -alkynylation of protected

2, -deoxyadenosine [J] .Tetrahedron Letters, 2009, (65): 4085-4091, with a substituted phenethyl m

Alkynyl easily catalyst Pd / CaC03, Fe2 (CO) 9, Pd (OAc) 2 and the like produce cis compound to catalytic reduction. The reaction follows the formula:

Figure CN103992212AD00052

Advantage of this method is stereospecific reduction of alkynes in the catalyst, to overcome the phenomenon of cis-trans isomerization of the Wittig reaction, but the reaction requires at _78 ° C, is not conducive to the operation, and the reagent sources difficult, expensive than high cost increase is not conducive to mass production.

[0007] ③ Belluci G, Chiappe C, Moro G L0.Crown ether catalyzed stereospecificsynthesis of Z_and E-stilbenes by Wittig reaction in a solid-liquid two-phasessystem [J] .Tetrahedron Letters, 1996, (37): 4225-4228 using Pd (PPh3) 4 as catalyst, an organic zinc reagent with a halide compound of cis-coupling reaction formula as follows:

Figure CN103992212AD00053

The advantage of this method is that selective, high yield to give cis; deficiency is difficult to handle, the catalyst is expensive.

[0008] ④ new Wang, Zhangxue Jing, Zhou Yue, Zouyong Shun, trans-3,4 ‘, 5-trihydroxy-stilbene China Pharmaceutical Synthesis, 2005, 14 (4);. 204-208, reported that the trans compound of formula was dissolved in DMSO solution at a concentration dubbed, ultraviolet irradiation was reacted at 365nm, converted into cis compounds, see the following reaction formula:

Figure CN103992212AD00061

However, the concentration of the solution preparation method, the reaction time is more stringent requirements.

Figure CN103992212AD00062

The synthesis of cis-alkenyl benzene Maude application embodiments Example 1 A synthesis of cis-alkenyl Maude benzene and benzene-cis-ene prepared Maude, the reaction was carried out according to the following scheme:

Figure CN103992212AD00101

Specific preparation process steps performed in the following order:

(O methylation reaction

The 195.12g (Imol) of 3, 5-hydroxy-4-isopropyl benzoic acid, 414.57g (3mol) in DMF was added 5000ml anhydrous potassium carbonate, mixing, stirred at room temperature, then cooled in an ice-salt bath next, slowly added dropwise 425.85g (3mol) of iodomethane, warmed to room temperature after the addition was complete, the reaction 2h, after completion of the reaction was stirred with water, extracted with ethyl acetate, and concentrated to give 3,5-dimethoxy-4- isopropyl benzoate; yield 93%, purity of 99%.

[0033] (2) a reduction reaction

3000ml tetrahydrofuran and 240g (Imol) 3,5-dimethoxy-4-isopropyl benzoate, 151.40g (4mol) mixing at room temperature sodium borohydride was stirred and heated to reflux was slowly added dropwise 400ml methanol, reaction 4h, was added 3L of water was stirred, extracted with ethyl acetate, washed with water, the solvent was removed by rotary evaporation to give a white solid, to give 3,5-dimethoxy-4-isopropylbenzene methanol; 96% yield purity was 99%.

[0034] (3) the oxidation reaction

The 212g (ImoI) of 3,5-dimethoxy-4-isopropylbenzene methanol, DMSO 800ml and 500ml of acetic anhydride were mixed and stirred at rt After 2h, stirred with water, extracted with ethyl acetate, washed with water, dried , and concentrated to give 3,5-dimethoxy-4-isopropyl-benzaldehyde; 94% yield, 99% purity.

[0035] (4) a condensation reaction

The mixture was 209.18g (lmol) of 3,5-dimethoxy-4-isopropyl-benzoic awake and 136.15g (Imol) phenylacetic acid was added 5000ml of acetic anhydride, stirred to dissolve, sodium acetate was added 246.09g , heating to 135 ° C, the reaction after 6h, cooled to room temperature after adjusting the dilute acid 2 was added, extracted with ethyl acetate, the pH was concentrated, added saturated sodium bicarbonate solution adjusted to pH 7, stirred 2h, and extracted with dichloromethane , adding dilute aqueous hydrochloric acid pH 2, the yellow solid was filtered, to obtain 3,5-dimethoxy-4-isopropyl-stilbene acid; 96% yield, 80% purity.

[0036] (5) decarboxylation reaction

The 327g (Imol) of 3,5-dimethoxy-4-isopropyl-stilbene acid and 384g (6mol) of copper powder were added to 5000ml of quinoline, 180 ° C reaction 3h, cooled to room temperature ethyl acetate was added with stirring, filtered, and the filtrate was washed with dilute hydrochloric acid to the aqueous layer was colorless and the aqueous phase was extracted with ethyl acetate inverted, the organic layers were combined, washed with water and saturated brine until neutral, i.e., spin-dried to give 3,5 – dimethoxy-4-isopropyl-stilbene; 92% yield, 77% purity.

[0037] (6) Demethylation

The 282.32g (Imol) of 3,5-dimethoxy-4-isopropyl-stilbene 4000ml toluene was placed in an ice bath and stirring, was cooled to 0 ° C, and dissolved slowly added 605.9g (5mol after) in N, N- dimethylaniline, was added 666.7g (5mol) of anhydrous aluminum chloride. after stirring for 0.5h, warmed to room temperature, the reaction was heated to 100 ° C 2h, cooled to 60 ° C , hot toluene layer was separated, diluted hydrochloric acid was added to the aqueous phase with stirring to adjust the PH value of 2, extracted with ethyl acetate, washed with water, and concentrated to give the cis-alkenyl benzene Modesto; crude yield 95%, purity 74 %.After separation by column chromatography using 300-400 mesh silica gel, benzene-cis-ene was isolated Maude pure, 68% yield, 98.5% purity. The resulting cis-alkenyl benzene Maud NMR shown in Figure 1, NMR data are as follows:

1HNMR (CDCl3, 500 Hz, δ: ppm), 7.255 (m, 5H), 6.558 (d, 1H), 6.402 (d, 1H), 6.218 (s, 2H), 4.872 (s, 2H), 3.423 (m , 1H), 1.359 (q, 6H). Coupling constants / = 12.

[0038] trans-alkenyl benzene Maud NMR shown in Figure 2, the following NMR data:

1HNMR (CDCl3, 500 Hz, δ: ppm), 7.477 (d, 2H), 7.360 (t, 2H), 6.969 (q, 2H), 6.501 (s, 1H), 4.722 (s, 2H), 3.486 (m , 1H), 1.380 (t, 6H). Coupling constants / = 16.

[0039] HPLC conditions a cis alkenyl benzene Maude pure product: column was Nucleosil 5 C18; column temperature was 20 ° C; detection wavelength 318nm; mobile phase consisting of 50:50 by volume of acetonitrile and water; flow rate It was 0.6mL / min, injection volume of 5 μ L; cis phenalkenyl Maude 18.423min retention time of a peak in an amount of 96.39%, see Figure 3. Trans phenalkenyl Maude 17.630min retention time of a peak, the content was 99.8%, see Figure 4.After mixing the two, trans-alkenyl benzene Maude 17.664min retention time of the peak, cis-alkenyl benzene Maude 18.458min retention time of the peak, see Figure 5.

PATENT

https://patents.google.com/patent/CN103172497A/en

Figure CN103172497AC00021

phenalkenyl Maude is a natural product, a metabolite as to be symbionts.Phenalkenyl Maud Escherichia coli, Staphylococcus aureus has a very significant inhibitory effect, in addition, there is a styrenic Maude suppression of inflammation and its reactive derivative with immunomodulating activity. Alkenyl benzene Modesto topical ointment as an active ingredient, as a class of drugs has been completed two clinical treatment of psoriasis and eczema, the results of ongoing clinical phase III clinical studies, it has been shown to be completed in both psoriasis and eczema clearly effect, together with a styrenic Maude is a non-hormonal natural small molecule compounds, can be prepared synthetically prepared, therefore, it exhibits good market prospect.

[0004] a styrenic Maude initial synthesis route is as follows:

[0005]

Figure CN103172497AD00041

[0006] The reaction conditions for each step: 1) isopropanol, 80% sulfuric acid, 60 ° C, 65% .2) sodium borohydride, boron trifluoride, tetrahydrofuran, 0 ° C, 90% .3). of thionyl chloride, heated under reflux, 85% .4). triethyl phosphate, 120 ° C, 80% .5). benzaldehyde, sodium hydride, 85% .6) pyridine hydrochloride, 190 ° C, 60 %.

[0007] The chemical synthesis route, although ultimately obtained a styrenic Maude, but the overall yield is low, part of the reaction step is not suitable for industrial production, due to process conditions result in the synthesis of certain byproducts produced is difficult to remove impurities, difficult to achieve the quality standard APIs.

Preparation of 4-isopropyl-dimethoxy-benzoic acid [0011] 1,3,5_

[0012] 1000 l reactor 200 liters of 80% sulfuric acid formulation (V / V), the temperature was lowered to room temperature, put 80 kg 3,5_-dimethoxybenzoate ,, stirring gradually warmed to 60 ° C, in was added dropwise within 25 kg of isopropanol I hour, the reaction was complete after 5 hours, 500 liters of hot water, filtered, the filter cake was washed with a small amount of hot water I th, crushed cake was removed and dried. The dried powder was recrystallized from toluene, the product was filtered to give 78 kg `, yield 86%. Preparation 2,3,5_ dimethoxy-4-isopropylbenzene methanol

[0013] 1000 l reactor was added 50 kg 3,5_ _4_ isopropyl dimethoxy benzoic acid, 24 kg of potassium borohydride, 400 l of THF, at room temperature was slowly added dropwise 65 kg BF3.Et2O was stirred 12 hours, the reaction was complete, pure water was added dropwise to destroy excess BF3, filtered, concentrated to dryness, methanol – water to give an off-white recrystallized 40.3 kg, yield 90.1%.

[0014] Preparation of 3,3,5-_ ■ methoxy _4- isopropyl group gas section

[0015] 1000 l autoclave, 100 kg of 3,5-dimethoxy-4-isopropylbenzene methanol, 220 l of DMF, 0 ° C and added dropwise with stirring and 50 l of thionyl chloride, 24 hours after the reaction was complete, 300 liters of water and 300 liters of ethyl acetate, the aqueous phase was stirred layered discharged, and then washed with 200 liters of water was added 3 times, until complete removal of DMF, was added concentrated crystallized from petroleum ether to give 98 kg of white solid was filtered and dried a yield of 91%.

Preparation of methyl-dimethoxy-4-isopropylbenzene of diethyl [0016] 4,3,5_

[0017] 500 l autoclave, 98 kg 3,5_ _4_ isopropyl dimethoxy benzyl chloride and 120 l of triethyl phosphite, the reaction at 120 ° C 5h, fear distilled off under reduced pressure, the collection 145-155 ° C / 4mmHg fear minutes, cured at room temperature to give a colorless light solid was 118 kg, yield 81.6%.

, 3- [0018] 5, E-1 _ ■ methoxy-2-isopropyl-5- (2-phenylethyl lean-yl) – benzene

[0019] 500 l autoclave, 33 kg 3,5_-dimethoxy-4-isopropylbenzene acid diethyl ester, 10.8 kg of benzaldehyde, and 120 l of tetrahydrofuran, at 40 ° C, and nitrogen with stirring, was added dropwise a solution of 11.8 kg potassium tert-butoxide in 50 liters of tetrahydrofuran, the temperature dropping control not to exceed 50 ° C. after the dropwise addition stirring was continued for I h, the reaction was complete, 150 liters of ethyl acetate and extracted , washed twice with 150 liters of water, 100 l I washed with brine, and the organic phase was dried and concentrated, methanol – water (I: D as a white crystalline solid 25.3 kg, yield 91%.

[0020] 6> 1, 3 ~ _ ■ Light-2-isopropyl-5- (2-phenylethyl lean-yl) – benzene (I), (De Dae dilute benzene)

[0021] 100 l autoclave, 10 kg 1,3_-dimethoxy-2-isopropyl-5- (2-styryl) benzene _ pyridine hydrochloride and 25 kg nitrogen atmosphere was heated to 180 -190 ° C, stirred for 3 hours after the reaction was completed, 20 l HCl (2N) cooling to 100 ° C, and 20 liters of ethyl acetate the product was extracted, dried and concentrated to give the product 7.3 kg, 83% yield.

[0022] The method for purifying:

[0023] 100 l added to the reaction vessel 15.5 kg of crude product and 39 liters of toluene, heated to the solid all dissolved completely, filtered hot and left to crystallize, after crystallization, filtration, the crystals with cold toluene 10 washed liter at 60 ° C, protected from light vacuo dried for 24 hours, to obtain 14 kg of white needle crystals, yield 90%.

CLIP

https://www.eosmedchem.com/article/237.html

Design new synthesis of Route of Benvitimod

Nov 26, 2018
1.Benvitimod and intermediates
Benvitimod 79338-84-4  intermediate: 1999-10-5
Benvitimod 79338-84-4  intermediate: 2150-37-0
Benvitimod 79338-84-4  intermediate: 344396-17-4
Benvitimod 79338-84-4  intermediate: 344396-18-5
Benvitimod 79338-84-4  intermediate: 344396-19-6
Benvitimod 79338-84-4  intermediate: 1080-32-6
Benvitimod 79338-84-4  intermediate: 678986-73-7
Benvitimod 79338-84-4  intermediate: 55703-81-6
Benvitimod 79338-84-4  intermediate: 1190122-19-0
Benvitimod 79338-84-4  intermediate: 443982-76-1
Benvitimod 79338-84-4  intermediate: 100-52-72.ROS-Benvitimod
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(2)
3.
Name: Benvitimod
CAS#: 79338-84-4
Chemical Formula: C17H18O2
Exact Mass: 254.1307
Molecular Weight: 254.329
Elemental Analysis: C, 80.28; H, 7.13; O, 12.58

References

  1. ^ Joyce SA; Brachmann AO; Glazer I; Lango L; Schwär G; Clarke DJ; Bode HB (2008). “Bacterial biosynthesis of a multipotent stilbene”. Angew Chem Int Ed Engl47 (10): 1942–5. doi:10.1002/anie.200705148PMID 18236486.
  2. ^ Hu, K; Webster, JM (2000). “Antibiotic production in relation to bacterial growth and nematode development in Photorhabdus–Heterorhabditis infected Galleria mellonella larvae”. FEMS Microbiology Letters189 (2): 219–23. doi:10.1111/j.1574-6968.2000.tb09234.xPMID 10930742.
  3. ^ “New Topical for Mild to Moderate Psoriasis in the Works”Medscape. March 5, 2017.
  4. https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fanie.201814016&file=anie201814016-sup-0001-misc_information.pdf

///Benvitimod, Tapinarof, WBI-1001, тапинароф , تابيناروف , 他匹那罗 , Welichem Biotech, Stiefel Laboratories, Shenzhen Celestial Pharmaceuticals,CHINA 2019 , Psoriasis, Tianji Pharma, Dermavant Sciences, PHASE 3

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