CN117510517A - Preparation method of PDE4B inhibitor BI-1015550 - Google Patents
Preparation method of PDE4B inhibitor BI-1015550 Download PDFInfo
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- CN117510517A CN117510517A CN202311451284.1A CN202311451284A CN117510517A CN 117510517 A CN117510517 A CN 117510517A CN 202311451284 A CN202311451284 A CN 202311451284A CN 117510517 A CN117510517 A CN 117510517A
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- Prior art keywords
- dihydrothieno
- methylthio
- methanol
- pyrimidin
- amino
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- 101000988424 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4B Proteins 0.000 title claims abstract description 13
- 102100029168 cAMP-specific 3',5'-cyclic phosphodiesterase 4B Human genes 0.000 title claims abstract description 13
- 239000003112 inhibitor Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- -1 1-amino-4-methylbenzenesulfonic acid cyclobutane methanol Chemical compound 0.000 claims abstract description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 11
- 239000012065 filter cake Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- AJXJCHRCLIWVKW-UHFFFAOYSA-N 4-chloro-2-methylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidine Chemical compound ClC1=NC(SC)=NC2=C1SCC2 AJXJCHRCLIWVKW-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 5
- JDJSZEVADPIWKL-UHFFFAOYSA-N 2-methylsulfanyl-6,7-dihydro-1h-thieno[3,2-d]pyrimidin-4-one Chemical compound N1C(SC)=NC(=O)C2=C1CCS2 JDJSZEVADPIWKL-UHFFFAOYSA-N 0.000 claims description 3
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical group CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 5
- 239000002904 solvent Substances 0.000 claims 5
- 238000010009 beating Methods 0.000 claims 4
- 238000000746 purification Methods 0.000 claims 4
- 238000001953 recrystallisation Methods 0.000 claims 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 1
- 241000872931 Myoporum sandwicense Species 0.000 claims 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 239000004210 ether based solvent Substances 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000003208 petroleum Substances 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- QYHFIVBSNOWOCQ-UHFFFAOYSA-N selenic acid Chemical compound O[Se](O)(=O)=O QYHFIVBSNOWOCQ-UHFFFAOYSA-N 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 abstract description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 abstract description 6
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 abstract description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 8
- 208000005069 pulmonary fibrosis Diseases 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 4
- 230000003510 anti-fibrotic effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000003176 fibrotic effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 2
- 229960001164 apremilast Drugs 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 2
- 229960002586 roflumilast Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 208000037851 severe atopic dermatitis Diseases 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of a PDE4B inhibitor BI-1015550. The synthetic method comprises the following reaction steps: from 2- (methylthio) -6, 7-dihydrothieno [3,2-d]The pyrimidine-4-alcohol is halogenated and then reacts with 1-amino-4-methylbenzenesulfonic acid cyclobutane methanol to obtain a key intermediate [1- [ (2- (methylthio) -6, 7-dihydro-thieno [3,2-d ]]Pyrimidin-4-yl) amino groups]Cyclobutyl group]Methanol, oxidized and finally reacted with 5-chloro-2- (piperidin-4-yl) pyrimidine hydrochloride to give compound BI-1015550.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and relates to a preparation method of a PDE4B inhibitor BI-1015550.
Background
Fibrosis (fibrosis) is a general term for a large group of diseases which can occur in almost all human tissues, and fibrotic diseased tissues and organs gradually lose normal function, severely affecting the quality of life of the patient, until life is endangered. Taking lung fibrosis as an example, the fibrotic tissue loses the original elasticity, so that the expansion and contraction of the lung become more and more difficult during breathing, the vital capacity is reduced, and the activity of a patient is seriously weakened. Pulmonary fibrosis is a common chronic pulmonary disease, its incidence rises year by year, bringing great trouble to the life and health of patients. Currently, methods of treatment for pulmonary fibrosis are limited, and most patients can only alleviate symptoms by supportive treatment. Therefore, the study and development of new drugs to treat pulmonary fibrosis is very important for patients.
The first class of PDE4 inhibitors, roflumilast (roflumilast), was approved by the united states Food and Drug Administration (FDA) in 2011 for use in reducing the risk of chronic obstructive pulmonary disease (copd) weighting. Another compound, oral apremilast (apremilast), was approved for the treatment of psoriatic arthritis and plaque psoriasis in 2014 (U.S. food and drug administration, 2017). The third PDE4 inhibitor, cliborole (cricabolole), was available in 2016 for topical treatment of moderate to severe atopic dermatitis (U.S. food and drug administration, 2016), none of which showed preferential inhibition of the four PDE4 enzyme subtypes (a-D). PDE4 inhibitors induce emesis, a well known gastrointestinal side effect that limits its use. The anti-fibrotic potential of PDE4 inhibitors has not been explored clinically until now. Oral phosphodiesterase 4B (PDE 4B) inhibitors can treat Idiopathic Pulmonary Fibrosis (IPF) and inflammation associated with progressive fibrotic interstitial lung disease. This therapy was identified as monotherapy and combined with existing anti-fibrotic therapies to analyze its efficacy in slowing down the rate of lung function decline in IPF patients.
BI 1015550 acts as an oral PDE4B inhibitor, having both anti-fibrotic and anti-inflammatory effects, and thus has the potential to address both pulmonary fibrosis and concomitant inflammation. Meanwhile, the inhibitor has priority on enzyme inhibition of PDE4B, and researches show that the preferential inhibition of PDE4B can maintain the curative effect of treating pulmonary fibrosis and can avoid gastrointestinal adverse reaction. Currently, BI 1015550 has been granted breakthrough treatment approval by the united states Food and Drug Administration (FDA) at month 2 2022. Phase III clinical trials will be initiated in the future to further investigate the efficacy of BI 1015550 in treating patients with Idiopathic Pulmonary Fibrosis (IPF) and Progressive Pulmonary Fibrosis (PPF).
Disclosure of Invention
In view of the above, the preparation of the PDE4B inhibitor BI-1015550 is very important. The inventor solves the technical problem of the compound through experimental study, and the reaction route is as follows:
the specific steps of the synthesis scheme are as follows:
1) Preparation of 4-chloro-2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidine (2) from starting 2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-ol by halogenation
2) The 4-chloro-2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidine (2) obtained in step 1) is reacted with 1-amino-4-methylbenzenesulfonic acid cyclobutanemethanol to give the compound [1- [ (2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol (3)
3) The [1- [ (2- (methylsulfanyl) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol (3) obtained in step 2) is oxidized to give the compound [1- [ (2- (methylsulfinyl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol (4)
4) Specific experimental mode of the compound [1- [ (2- (methylsulfinyl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol (4) and 5-chloro-2- (piperidin-4-yl) pyrimidine hydrochloride were reacted to obtain compound BI-1015550
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Step A
To 2- (methylthio) -6, 7-dihydrothieno [3,2-d]Pyrimidin-4-ol (1 g,5 mmol) in CH 3 POCl was added to the solution in CN (30 mL) 3 (5 mL). The resulting mixture was stirred at 90 ℃ for 3h, then cooled to room temperature and poured into water. Filtering the precipitate to obtain the compound 4-chloro-2- (methylthio) -6, 7-dihydrothieno [3,2-d ]]Pyrimidine (473 mg, 43% yield), LC-MS (ESI): m/z=218.7 [ m+h ]] + .
Step B
Intermediate 4-chloro-2- (methylthio) -6, 7-dihydrothieno [3,2-d]Pyrimidine (186 g, 850 mmol) and Compound 1-Amino-4-methylbenzenesulfonic acid cyclobutanemethanol (129 g,937 mmol) was successively charged into a multi-necked vessel equipped with a condenser, a thermocouple thermometer and a nitrogen line. Acetonitrile (900 mL) and triethylamine (594 mL,4.26 mol) were then added at 22 ℃ and the mixture stirred at 76 ℃ for 12h. Water (1.2L) was slowly added over a period of 20min, the mixture was inoculated with crystals of the reaction compound (0.3 g) at 40℃and then cooled to 25℃over a period of 2h. The mixture was stirred at room temperature for a further 12h and the resulting solid was collected by filtration. The filter cake was rinsed with a 2:1 water/MeCN mixture (400 mL) and water (200 mL). The resulting solid was dried under vacuum at 50℃for 12h to give the compound [1- [ (2- (methylthio) -6, 7-dihydrothieno [3,2-d ]]Pyrimidin-4-yl) amino groups]Cyclobutyl group]Methanol (121 g, 50% yield). LC-MS (ESI): m/z=283.4 [ m+h ]] + .
Step C
The compound [1- [ (2- (methylthio) -6, 7-dihydrothieno [3,2-d ]]Pyrimidin-4-yl) amino groups]Cyclobutyl group]Methanol (122 g,429 mmol), (S) - (-) -1,1' -bi-2-naphthol (12.4 g,42.9 mmol), dichloromethane (608 mL), ti (OiPr) 4 (6.54 mL,21.4 mmol) and water (7.72 mL, 428 mmol) were added to the multi-necked flask and stirred at 20℃under nitrogen for 1h. T-butyl peroxide (70% aqueous solution, 62.3mL, 470 mmol) was added in one portion at 21 ℃; the mixture became completely homogeneous and the temperature increased to about 40 ℃. The mixture was allowed to reach normal room temperature, stirred for 1.5h and filtered. Washing the filter cake with isopropyl acetate twice (243 mL each time), and air-drying the filter cake in the filter for more than 6h to obtain the compound [1- [ (2- (methylsulfinyl) -5-oxo-6, 7-dihydrothieno [3,2-d ]]Pyrimidin-4-yl) amino groups]Cyclobutyl group]Methanol (108 g, 80% yield). LC-MS (ESI): m/z=315.4 [ m+h ]] + .
Step D
The compound [1- [ (2- (methylsulfinyl)Phenyl) -5-oxo-6, 7-dihydrothieno [3,2-d]Pyrimidin-4-yl) amino groups]Cyclobutyl group]Methanol (92 g,29 mmol), 5-chloro-2- (piperidin-4-yl) pyrimidine hydrochloride (160 g,305 mmol), tetrahydrofuran (484 mL), water (121 mL) and DIPEA (N, N-diisopropylethylamine, 127mL,727 mmol) were all charged under nitrogen to a 3L round bottom flask and heated to 65 ℃ for 3h. Then water (1196 mL,13mL/g of the compound [1- [ (2- (methylsulfinyl) -5-oxo-6, 7-dihydrothieno [3, 2-d) ] was added at a temperature of 65 ℃]Pyrimidin-4-yl) amino groups]Cyclobutyl group]Methanol) and stirred for 2h while cooling to 20 ℃, the mixture was filtered and the filter cake was washed twice with acetone. The filter cake was then dried on the funnel overnight to give the title compound BI-1015550 (118 g, 90% yield). LC-MS (ESI): m/z=448.97 [ m+h ]] + . 1 H NMR(400MHz,CDCl 3 )δ1.74-1.96(m,4H),2.03-2.27(m,4H),2.38(q,Hz,2H),2.93-3.12(m,4H),3.12-3.22(m,1H),3.28-3.39(m,1H),3.53-3.65(m,1H),3.80(d,J＝5.6Hz,2H),4.42(t,J＝5.2Hz,1H),4.82(br,2H),6.47(s,1H),8.62(s,2H)；
The above examples are only for illustrating embodiments of the present invention, but the present invention is not limited to the above examples only. The invention is capable of numerous modifications and adaptations without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents.
Claims (5)
1. A preparation method of a PDE4B inhibitor BI-1015550, which is characterized by comprising the following specific steps:
(1) Preparation of 4-chloro-2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidine from starting 2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-ol by halogenation
(2) Reacting the 4-chloro-2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidine obtained in step (1) with 1-amino-4-methylbenzenesulfonic acid cyclobutanemethanol to obtain the compound [1- [ (2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol
(3) The [1- [ (2- (methylthio) -6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol obtained in the step (2) is oxidized to obtain the compound [1- [ (2- (methylsulfinyl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol
(4) The compound [1- [ (2- (methylsulfinyl) -5-oxo-6, 7-dihydrothieno [3,2-d ] pyrimidin-4-yl) amino ] cyclobutyl ] methanol was reacted with 5-chloro-2- (piperidin-4-yl) pyrimidine hydrochloride to give compound BI-1015550.
2. The process for preparing PDE4B inhibitors BI-1015550 according to claim 1, wherein in step (1), the reaction temperature is from 50 to 120℃and the reaction time is from 0 to 5 hours, the halogenating agent in the reaction is selected from HCl, SOCl 2 、PCl 3 、PCl 5 、POCl 3 One or more of them. The solvent is selected from one or more of ether solvents such as THF, DME, MTBE, diethyl ether and butyl ether, and hydrocarbon solvents such as n-hexane, n-heptane, n-pentane, petroleum ether, benzene and toluene. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
3. The process for preparing a PDE4B inhibitor BI-1015550 as claimed in claim 1, wherein in step (2), the reaction temperature is selected from 10-200deg.C, the time is selected from 0-72h, and the solvent is selected from one or more of N, N-Dimethylformamide (DMF), dichloromethane, etc. The alkaline agent is one or more selected from sodium carbonate, potassium carbonate, triethylamine, sodium hydroxide, potassium hydroxide, etc. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
4. The process for preparing a PDE4B inhibitor BI-1015550 according to claim 1, wherein in step (3), the reaction temperature is from 25 to 70 ℃ and the time is from 0 to 24 hours, and the solvent is one or more selected from methanol, methylene chloride, ethanol, water, formonitrile, N-dimethylformamide, dimethyl sulfoxide and the like. The oxidant is selected from tert-butyl peroxide, hydrogen peroxide, oxygen and N 2 O 4 、NaIO 4 One or more of the following. The catalyst is selected from alumina, ti (OiPr) 4 One or more of selenic acid, selenium dioxide, etcA kind of module is assembled in the module and the module is assembled in the module. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
5. The process for the preparation of a PDE4B inhibitor BI-1015550 according to claim 1,
in the step (4), the reaction temperature is selected from 10-200 ℃, and the solvent is selected from acetonitrile, THF, 1, 4-dioxane and H 2 O, DMSO, DCM, 1, 2-dichloroethane. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.
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