WO2018137679A1 - Process for the Preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile - Google Patents
Process for the Preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile Download PDFInfo
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- VRPJIFMKZZEXLR-UHFFFAOYSA-N CC(C)(C)OC(NCC(O)=O)=O Chemical compound CC(C)(C)OC(NCC(O)=O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- IXHCKAZSQGVXKF-UHFFFAOYSA-O CC(c(cc(cc1)F)c1C(N(C)CC(C=C(C#N)[NH2+]C)=N)=O)Oc1c(N)ncc(Br)c1 Chemical compound CC(c(cc(cc1)F)c1C(N(C)CC(C=C(C#N)[NH2+]C)=N)=O)Oc1c(N)ncc(Br)c1 IXHCKAZSQGVXKF-UHFFFAOYSA-O 0.000 description 1
- HPMMSQUICAYILZ-UHFFFAOYSA-N CNCc1n[n](C)c(C#N)c1 Chemical compound CNCc1n[n](C)c(C#N)c1 HPMMSQUICAYILZ-UHFFFAOYSA-N 0.000 description 1
- DQYRXTZYTCLLIU-PKEIRNPWSA-N C[C@H](C(CC(OC)F)=C)Oc1c(N)ncc([Br]=C)c1 Chemical compound C[C@H](C(CC(OC)F)=C)Oc1c(N)ncc([Br]=C)c1 DQYRXTZYTCLLIU-PKEIRNPWSA-N 0.000 description 1
- RJCFBGXBCPDEOT-MRXNPFEDSA-N C[C@H](c(cc(cc1)F)c1C(N(C)Cc1n[n](C)c(C#N)c1)=O)Oc1c(NC(CNC(OC(C)(C)C)=O)=O)ncc(Br)c1 Chemical compound C[C@H](c(cc(cc1)F)c1C(N(C)Cc1n[n](C)c(C#N)c1)=O)Oc1c(NC(CNC(OC(C)(C)C)=O)=O)ncc(Br)c1 RJCFBGXBCPDEOT-MRXNPFEDSA-N 0.000 description 1
- RWCKJUDAWPQAAY-GFCCVEGCSA-N C[C@H](c(cc(cc1)F)c1C(N(C)Cc1n[n](C)c(C#N)c1-1)=O)Oc2cc-1cnc2NC(CN)=O Chemical compound C[C@H](c(cc(cc1)F)c1C(N(C)Cc1n[n](C)c(C#N)c1-1)=O)Oc2cc-1cnc2NC(CN)=O RWCKJUDAWPQAAY-GFCCVEGCSA-N 0.000 description 1
- OJAFDDUJGHSCJZ-OAHLLOKOSA-N C[C@H](c(cc(cc1)F)c1C(N(C)Cc1n[n](C)c(C#N)c1-1)=O)Oc2cc-1cnc2NC(CNC(OC(C)(C)C)=O)=O Chemical compound C[C@H](c(cc(cc1)F)c1C(N(C)Cc1n[n](C)c(C#N)c1-1)=O)Oc2cc-1cnc2NC(CNC(OC(C)(C)C)=O)=O OJAFDDUJGHSCJZ-OAHLLOKOSA-N 0.000 description 1
- PJWZSKRVCOPPSJ-NGCURENTSA-N C[C@H](c1cc(F)ccc1C(N(C)CC(/C=C(/C#N)\NC)=N)=O)Oc1c(NC(CNC(OC(C)(C)C)=O)=O)ncc(Br)c1 Chemical compound C[C@H](c1cc(F)ccc1C(N(C)CC(/C=C(/C#N)\NC)=N)=O)Oc1c(NC(CNC(OC(C)(C)C)=O)=O)ncc(Br)c1 PJWZSKRVCOPPSJ-NGCURENTSA-N 0.000 description 1
- RSDAPPYFQSNMQD-GFCCVEGCSA-N C[C@H](c1cc(F)ccc1C(N(C)Cc1n[n](C)c(C#N)c1)=O)Oc1c(N)ncc(Br)c1 Chemical compound C[C@H](c1cc(F)ccc1C(N(C)Cc1n[n](C)c(C#N)c1)=O)Oc1c(N)ncc(Br)c1 RSDAPPYFQSNMQD-GFCCVEGCSA-N 0.000 description 1
- YAYLQOYIWCYZSC-QGZVFWFLSA-N C[C@H](c1cc(F)ccc1C(N(C)Cc1n[n](C)c(C#N)c1)=O)Oc1c(NC(CNC(OC(C)(C)C)=O)=O)ncc([Br]=C)c1 Chemical compound C[C@H](c1cc(F)ccc1C(N(C)Cc1n[n](C)c(C#N)c1)=O)Oc1c(NC(CNC(OC(C)(C)C)=O)=O)ncc([Br]=C)c1 YAYLQOYIWCYZSC-QGZVFWFLSA-N 0.000 description 1
- KDENGSZIXFSOJV-MRVPVSSYSA-N C[C@H](c1cc(F)ccc1C(O)=O)Oc1c(N)ncc([Br]=C)c1 Chemical compound C[C@H](c1cc(F)ccc1C(O)=O)Oc1c(N)ncc([Br]=C)c1 KDENGSZIXFSOJV-MRVPVSSYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile, to processes for its preparation.
- the invention provides a process for the preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile (Compound 7 in Formula (I) ) , which is characterized by using Compound 5 with Boc protecting group as Scheme 1:
- the invention provides the key intermediates for the preparing Compound 7:
- the invention provides a process for the preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile (Compound 7 in Formula (I) ) , which is characterized by using Compound 5 with Boc protecting group shown in Scheme 1:
- the invention provided a process of preparing Compound 7, the ester group of Compound 1 is hydrolyzed with NaOH in THF/Water or MeOH/Water or acetone/Water or acetonitrile/water or isopropanol/Water or EtOH/Water into Compound 2 in the Step (1) , and more preferably, in THF/Water or MeOH/Water.
- the invention provided a process of preparing Compound 7, the amide formation of Compound 2 and 3 optionally with a coupling reagent and in a non-reactive solvent, afforded Compound 4 in the Step (2) ;
- the coupling reagent is selected from HATU, EDC, DCC, BOP, T 3 P, or HOBt, and with DIEA or DIPEA;
- the non-reactive solvent is selected from DCM, DMF, or dioxane;
- the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA;
- the non-reactive solvent is selected from DCM, DMF, or dioxane.
- the invention provided a process of preparing Compound 7, Compoud 4 is reacted with Boc-Glycine optionally in the present of a coupling reagent and in a non-reactive solvent to afford Compound 5 in the Step (3) ; more preferably, the coupling reagent is selected from HATU, EDC, DCC, BOP, T 3 P, or HOBt, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane; most preferably, the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane.
- the coupling reagent is selected from HATU, EDC, or DCC, and with DIEA or DIPEA
- the non-reactive solvent is selected from DCM, DMF, or dioxane.
- the invention provided a process of preparing Compound 7, Compound 5 is intramolecularly cyclized into Compound 6 under palladium catalyzed condition in the Step (4) , more preferably, in the present of Pd (OAc) 2 , cataxiuma and KOAc, and in t-AmOH.
- the invention provided a process of preparing Compound 7, Compound 6 is deprotected under acidic condition such as HCl in MeOH or dioxane in the Step (5) .
- the invention provided a process of preparing Compound 7 in the Scheme 3:
- the invention provides the key intermediates for the preparing Compound 7:
- DMF means N, N-dimethylformamide.
- DCM dichloromethane
- HATU means 1- [Bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium 3-oxid hexafluorophosphate
- DIPEA or DIEA means diisopropyl ethylamine.
- DCC means Dicyclohexylcarbodiimide.
- EDC means N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride.
- THF means tetrahydrofuran
- EA means ethyl acetate.
- HOBt means hydroxybenzotriazole
- m-CPBA meta-Chloroperoxybenzoic acid.
- Boc-Gly-OH means N- (tert-Butoxycarbonyl) glycine.
- BOP means (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate.
- Pd (dppf) Cl 2 means [1, 1′-Bis (diphenylphosphino) ferrocene] dichloropalladium.
- T 3 P means n-propylphosphonoic anhydride
- Et 3 N means triethyl amine
- Fmoc Fluorenylmethyloxycarbonyl
- cataXium A means Di (1-adamantyl) -n-butylphosphine
- Pd (OAc) 2 means palladium acetate
Abstract
The present application disclosed a process for the preparing (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile, characterized by using Compound 5 with Boc protecting group, which is more suitable for industrial production.
Description
CROSS REFERENCE
This invention claims the benefit of U.S. Provisional Patent Application No. 62/499,395, filed on January 25, 2017, which is incorporated herein by reference in its entirety.
The present invention relates to (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile, to processes for its preparation.
Compound (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile is mentioned in WO2016/026423 and corresponds to the compound of the Formula (I) :
The synthetic procedure described in WO2016/026423, although suitable, regarded as disadvantageous for commercial production. There is a need for improved manufacturing methods of compound described in Formula (I) . In particular, there is a need to provide processes that fulfill one or more of the following criteria: scalable, safer, simpler, higher yielding and more economical when compared to known.
SUMMARY OF THE INVENTION
In the first aspect, the invention provides a process for the preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile (Compound 7 in Formula (I) ) , which is characterized by using Compound 5 with Boc protecting group as Scheme 1:
In the second aspect, the invention provides the key intermediates for the preparing Compound 7:
The initial designed synthesis of compound 7 in Formula (I) was described in Scheme 2. The protection of compound 1 with Boc-Glycine afforded compound A. The hydrolysis of compound A did not give the desire compound B, but generated compound C as the major product along with some compound 1. The protection of compound A with Fmoc-Glycine also afforded very low yield of desired product. Most of the Fmoc group was cleaved under various reaction conditions.
Scheme 2:
In one embodiment, the invention provides a process for the preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile (Compound 7 in Formula (I) ) , which is characterized by using Compound 5 with Boc protecting group shown in Scheme 1:
Scheme 1
in which includes the following steps:
(1) the ester group of Compound 1 is hydrolyzed into Compound 2;
(2) Compound 2 is coupled with Compound 3 to afford Compound 4;
(3) Compoud 4 is reacted with Boc-Glycine to generate Compound 5;
(4) Compound 5 is intramolecularly cyclized into Compound 6;
(5) Compound 6 is deprotected to afford Compound 7.
In one preferred embodiment, the invention provided a process of preparing Compound 7, the ester group of Compound 1 is hydrolyzed with NaOH in THF/Water or MeOH/Water or acetone/Water or acetonitrile/water or isopropanol/Water or EtOH/Water into Compound 2 in the Step (1) , and more preferably, in THF/Water or MeOH/Water.
In one preferred embodiment, the invention provided a process of preparing Compound 7, the amide formation of Compound 2 and 3 optionally with a coupling reagent and in a non-reactive solvent, afforded Compound 4 in the Step (2) ; more preferably, the coupling reagent is selected from HATU, EDC, DCC, BOP, T
3P, or HOBt, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane; most preferably, the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane.
In one preferred embodiment, the invention provided a process of preparing Compound 7, Compoud 4 is reacted with Boc-Glycine optionally in the present of a coupling reagent and in a non-reactive solvent to afford Compound 5 in the Step (3) ; more preferably, the coupling reagent is selected from HATU, EDC, DCC, BOP, T
3P, or HOBt, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane; most preferably, the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane.
In one preferred embodiment, the invention provided a process of preparing Compound 7, Compound 5 is intramolecularly cyclized into Compound 6 under palladium catalyzed condition in the Step (4) , more preferably, in the present of Pd (OAc)
2, cataxiuma and KOAc, and in t-AmOH.
In one preferred embodiment, the invention provided a process of preparing Compound 7, Compound 6 is deprotected under acidic condition such as HCl in MeOH or dioxane in the Step (5) .
In specific embodiment, the invention provided a process of preparing Compound 7 in the Scheme 3:
The ester group of Compound 1 was hydrolyzed with NaOH in THF/Water or MeOH/Water to give Compound 2. The amide formation of Compound 2 and 3 with HATU in DCM afforded Compound 4, which reacted with Boc-Glycine to generate Compound 5. The intramolecular cyclization of Compound 5 under palladium catalyzed condition afforded Compound 6. Deprotection of Boc group of Compound 6 led to the synthesis of Compound 7.
In anther embodiment, the invention provides the key intermediates for the preparing Compound 7:
Abbreviations
DMF means N, N-dimethylformamide.
DCM means dichloromethane.
HATU means 1- [Bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium 3-oxid hexafluorophosphate
DIPEA or DIEA means diisopropyl ethylamine.
DCC means Dicyclohexylcarbodiimide.
EDC means N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride.
THF means tetrahydrofuran.
EA means ethyl acetate.
HOBt means hydroxybenzotriazole.
m-CPBA means meta-Chloroperoxybenzoic acid.
Boc-Gly-OH means N- (tert-Butoxycarbonyl) glycine.
BOP means (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate.
Pd (dppf) Cl
2 means [1, 1′-Bis (diphenylphosphino) ferrocene] dichloropalladium.
T
3P means n-propylphosphonoic anhydride
Et
3N means triethyl amine
Fmoc means Fluorenylmethyloxycarbonyl
cataXium A means Di (1-adamantyl) -n-butylphosphine
Pd (OAc)
2 means palladium acetate
Example 1 (Compound 2)
To a solution of Compound 1 (500 mg) in methanol and water was added 5 equivalents of NaOH and the reaction was stirred at room temperature overnight. The reaction solution was heated to 45℃ for another 4 hours and cooled down to room temperature. The reaction then was worked out to give Compound 2 (400 mg) . MS m/z 355 [M+1] .
Example 2 Synthesis of (R) -2- (1- ( (2-amino-5-bromopyridin-3-yl) oxy) ethyl) -4-fluorobenzoic acid (Compound 2)
To a solution of compound 1 (10 g, 27 mmol) in MeOH (150 mL) were added a solution of NaOH (5.42 g, 13.55 mmol) in water (40 mL) . The mixture was heated at 40 ℃ for 10 h. Then cooled and evaporated under reduced pressure. The residue was added water (150 mL) and extracted with EA (50 mL) . The aqueous phase was adjusted to pH about 7 and extracted with EA (50 mL*3) . The combined organic phase was washed with brine, dried with Na
2SO
4 and evaporated under reduced pressure to provide compound 2 (9.5 g, 98.7%yield) as a light yellow solid.
1H-NMR (CD
3OD, 300 MHz) : δ 8.07-8.12 (m, 1H) , 7.50 (s, 1H) , 7.38-7.34 (m, 1H) , 7.15-7.09 (m, 1H) , 6.88 (s, 1H) , 6.49 (t, J=6.0 Hz, 1H) , 1.66 (dd, J=6.3 Hz, 3H) . MS m/z 355 [M+1] .
Example 2 (Compound 4)
To a solution of Compound 2 (100 mg) in DCM was added Compound 3, HATU, and DIEPA, the reaction was stirred overnight and workout to give desired product Compound 4 (100 mg) . MS m/z 487 [M+1] .
Example 3 Synthesis of (R) -2- (1- ( (2-amino-5-bromopyridin-3-yl) oxy) ethyl) -N- ( (5-cyano-1-methyl-1H-pyrazol-3-yl) methyl) -4-fluoro-N-methylbenzamide (Compound 4)
To a solution of compound 3 (8.4 g, 45.07 mmol) , HATU (17.12 g, 45.07 mmol) and DIEA (14.53 g, 112.68 mmol) in DMF (200 mL) was added compound 2 (10.0 g, 28.17 mmol) under N
2 with ice-water bath. The mixture was stirred overnight at room temperature. Water (500 mL) was was added and extracted with EA (100 mL*3) . The combined organic phase was washed with brine, dried with Na
2SO
4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA =2: 1 to 1: 1, v: v) to provide compound 4 (10.0 g, 73%yield) as an off-white solid.
1H-NMR (DMSO, 300 MHz) : δ= 7.35-7.54 (m, 3H) , 6.99-7.23 (m, 3H) , 6.09-6.29 (m, 2H) , 5.48-5.52 (m, 1H) , 4.66-4.75 (m, 1H) , 4.45-4.66 (m, 1H) , 3.92-3.95 (m, 3H) , 2.97 (s, 1H) , 2.76 (s, 1H) . MS: 488 [M+1]
+. MS m/z 487 [M+1] .
Example 4 (Compound 5)
To a solution of Compound 4 in dioxane were added Boc-Glycine, HATU and DIEA. The reaction was heated at 80℃ and followed by TLC until the completion. Worked out to give the desire product Compound 5. MS m/z 644 [M+1] .
Example 5 Synthesis of (R) -tert-butyl (2- ( (5-bromo-3- (1- (2- ( ( (5-cyano-1-methyl-1H-pyrazol-3-yl) methyl) (methyl) carbamoyl) -5-fluorophenyl) ethoxy) pyridin-2-yl) amino) -2-oxoethyl) carbamate (Compound 5)
A solution of compound 4 (10.5 g, 21.56 mmol) , Boc-Gly-OH (13.2 g, 75.46 mmol) , HATU (32.77 g, 96.24 mmol) and DIEA (16.68 g, 129 mmol) in dioxane (300 ml) was heated to 80 ℃ for 8 h under N
2. The solvent was removed under reduced pressure. Water (150 mL) was added and extracted with EA (100 ml*3) , the combined organic phase was washed with brine, dried with Na
2SO
4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA =2: 1, v: v) to provide compound 5 (9.0 g, 64.7%yield) as a yellow solid.
1H-NMR (DMSO, 400 MHz) : δ= 9.87-9.88 (d, J=1.6 Hz, 1H) , 7.65-7.69 (m, 1H) , 7.42-7.46 (m, 1H) , 7.14-7.25 (m, 1H) , 5.56-5.57 (m, 1H) , 4.36-4.75 (m, 2H) , 3.96-4.046 (m, 3H) , 3.96-4.06 (m, 2H) , 3.01 (s, 1H) , 2.84 (s, 2H) , 1.55 (d, J=4.4 Hz, 3H) , 1.40 (s, 1H) . MS m/z 644 [M+1] .
Example 6 (Compound 6)
To a solution of Compound 5 in t-AmOH were added Pd (OAc)
2, catax1 and KOAc. The reaction was heated to reflux for overnight to give desired product Compound 6. MS m/z 564 [M+1] .
Example 7 Synthesis of compound (6)
To a solution of compound 5 (7.0g, 10.87 mmol) in t-AmOH (200 mL) was added Pd(OAc) 2 (650 mg, 2.90 mmol) , cataxiuma (2.08 g, 5.80 mmol) and KOAc (5.35 g, 54.35 mmol) . The mixture was heated at 120 ℃ overnight under N
2. After cooled and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH =100: 1, v: v) to provide the yellow solid, then the solid was again purified by silica gel column chromatography (EA) to provide compound 6 (1.5g, 24.5%yield) as a yellow solid.
1H-NMR (CD3OD, 400 MHz) : δ= 7.96 (s, 1H) , 7.54-7.57 (m, 1H) , 7.40-7.43 (m, 1H) , 7.21 (s, 1H) , 7.10-7.13 (m, 1H) , 5.77 (t , J=6.0 Hz, 1H) , 4.39-4.51 (m, 2H) , 4.07-4.12 (m, 5H) , 3.12 (s, 3H) , 1.81 (dd , J=6.0 Hz, 3H) , 1.50 (s, 9H) . MS m/z 564 [M+1] .
Example 8 (Compound 7)
To compound 6 in DCM was added HCl (4N in dioxane, 2ml) at 0℃, the mixture was stirred at 0℃ for another 6 hr, stop the reaction and evaporated to be dry, to the residue was added water (10ml) , the mixture was extracted with DCM (2ml x2) , the DCM layer was discarded, the water layer was adjusted pH to 8-9 by NaOH (1N) and then filtered, the solid was washed by water (2ml) and dried to give the crude product, the crude product was purified by silica gel column chromatography (DCM: MeOH /30: 1 to 15: 1) to give the desired product as an off-white solid. MS m/z 464 [M+1] .
Example 9 (Compound 7)
A solution of compound 6 (2.2 g, 3.91 mmol) in DCM (10 mL) was added TFA (2 ml) , then the solution was stirred for 2 h at room temperature. The solution was evaporated under reduced pressure. Water (20 mL) was added and extracted with DCM (20 ml) , the aqueous phase was adjusted to pH about 8~9 and extracted with DCM (20*5) . The combined organic phase was dried over anhydrous Na
2SO
4. The solvent was evaporated under reduced pressure and the residue was purified by pre-HPLC to provide Compound 7 (340 mg, 18.9%yield) as a white solid.
1H-NMR (CD3OD, 400 MHz) : δ= 8.03 (d , J=1.6 Hz, 1H) , 7.52-7.55 (m, 1H) , 7.41-7.44 (m, 1H) , 7.23 (d , J=1.2 Hz, 1H) , 7.10-7.14 (m, 1H) , 5.78 (t , J=5.6 Hz, 1H) , 4.40-4.52 (m, 2H) , 4.10 (s, 3H) , 3.63 (s, 2H) , 3.13 (s, 3H) 1.80 (dd , J=6.0 Hz, 3H) . MS m/z 464 [M+1] .
Claims (8)
- A process for preparing of Compound 7, in which includes the following steps:(1) the ester group of Compound 1 is hydrolyzed into Compound 2;(2) Compound 2 is coupled with Compound 3 to afford Compound 4;(3) Compoud 4 is reacted with Boc-Glycine to generate Compound 5;(4) Compound 5 is intramolecularly cyclized into Compound 6;(5) Compound 6 is deprotected to afford Compound 7:
- The process of Claim1, wherein Compound 1 is hydrolyzed with NaOH in THF/Water or MeOH/Water or acetone/Water or acetonitrile/water or isopropanol/Water or EtOH/Water into Compound 2 in the Step (1) , and more preferably, in THF/Water or MeOH/Water.
- The process of Claim1, wherein the amide formation of Compound 2 and 3 optionally with a coupling reagent and in a non-reactive solvent, afforded Compound 4 in the Step (2) ; more preferably, the coupling reagent is selected from HATU, EDC, DCC, BOP, T 3P, or HOBt, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane; most preferably, the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane.
- The process of Claim1, wherein Compoud 4 is reacted with Boc-Glycine optionally in the present of a coupling reagent and in a non-reactive solvent to afford Compound 5 in the Step (3) ; more preferably, the coupling reagent is selected from HATU, EDC, DCC, BOP, T 3P, or HOBt, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane; most preferably, the coupling reagent is HATU, EDC, or DCC, and with DIEA or DIPEA; the non-reactive solvent is selected from DCM, DMF, or dioxane.
- The process of Claim1, wherein Compound 5 is intramolecularly cyclized into Compound 6 under palladium catalyzed condition in the Step (4) , more preferably, in the present of Pd (OAc) 2, cataxiuma and KOAc, and in t-AmOH.
- The process of Claim1, wherein Compound 6 is deprotected under acidic condition such as HCl in MeOH or dioxane in the Step (5) .
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