CN116768972A - Preparation method of carfilzomib intermediate - Google Patents
Preparation method of carfilzomib intermediate Download PDFInfo
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- CN116768972A CN116768972A CN202310746513.6A CN202310746513A CN116768972A CN 116768972 A CN116768972 A CN 116768972A CN 202310746513 A CN202310746513 A CN 202310746513A CN 116768972 A CN116768972 A CN 116768972A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- DDMPMIMTLBGEHT-HZMBPMFUSA-N tert-butyl n-[(2s)-4-methyl-1-[(2s)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)CO1 DDMPMIMTLBGEHT-HZMBPMFUSA-N 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000007530 organic bases Chemical class 0.000 claims abstract description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 claims description 11
- 108010021331 carfilzomib Proteins 0.000 claims description 11
- 229960002438 carfilzomib Drugs 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- JKAPWXKZLYJQJJ-UHFFFAOYSA-N 2,4-dichloro-6-methoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(Cl)=N1 JKAPWXKZLYJQJJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- -1 carfilzomib intermediate compound Chemical class 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 238000004321 preservation Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- VIWZVFVJPXTXPA-UHFFFAOYSA-N N-(2-Carboxymethyl)-morpholine Chemical compound OC(=O)CN1CCOCC1 VIWZVFVJPXTXPA-UHFFFAOYSA-N 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- HDYQLGLEPPGPEV-UHFFFAOYSA-N benzyl 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OCC1=CC=CC=C1 HDYQLGLEPPGPEV-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N epoxyketone group Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940000764 kyprolis Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a carfilzomib intermediate compound shown as a formula 3, which comprises the step of reacting a compound shown as a formula 1 with a compound shown as a formula 2 in a system containing organic base in the presence of condensing agents such as 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 4- (4, 6-dimethoxy-1, 3, 5-triazine-2-yl) -4-methylmorpholine hydrochloride (DMTMM) and the like to prepare the compound shown as the formula 3. The method has the advantages of short reaction time, high raw material conversion rate, simple post-treatment, less three wastes, high total yield and low EHS risk, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a carfilzomib intermediate.
Background
Carfilzomib (Carfilzomib) is a second generation protease inhibitor containing a tetrapeptide epoxyketone structure developed by the company Onyx Pharma, and approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory multiple myeloma at 7, 2012 under the trade name kypro lis.
Carfilzomib is chemically named { (2S) -2- [ (morpholin-4-yl) acetamido ] -4-phenylbutyryl } -L-leucyl-N1- { (2S) -1[ (2R) -2-methyl-epoxy ethyl-2-yl ] -4-methyl-1-oxopentan-2-yl } -L-phenylalaninamide, and its structure is shown below:
carfilzomib
CN102286070B discloses a method for synthesizing carfilzomib, the reaction formula is as follows:
in the synthesis method, an intermediate compound 3 is obtained by taking a compound 1 as a starting material and condensing with a compound 2 under the action of a condensing agent 1H-benzotriazole-1-oxygen tripyrrolidine phosphonium hexafluorophosphate (PyBOP). The method is a common method for preparing the carfilzomib intermediate compound 3 at present, but the method still has some problems when being used for mass production. For example, the method uses expensive PyBOP as condensing agent, resulting in higher production cost; in addition, the method has complicated post-treatment mode, usually requires multiple extraction and washing, generates a large amount of three wastes, and has low yield of only 74 percent. Therefore, the research and development of the preparation method of the carfilzomib intermediate compound 3 has the advantages of low cost, simple post-treatment process, less three wastes, high yield and suitability for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of a carfilzomib intermediate, which is a compound 3 (or a compound of formula 3). The method selects cheap and easily available 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT) and 4- (4, 6-dimethoxy-1, 3, 5-triazine-2-yl) -4-methylmorpholine hydrochloride (DMTMM) as condensing agents, has high product purity, simple and convenient post-treatment operation, greatly reduces three wastes, improves the total yield, and is particularly suitable for industrial production.
To achieve the object of the present invention, the present invention provides the following embodiments:
in one embodiment, the invention provides a method for preparing a compound of formula 3 as a carfilzomib intermediate, wherein the reaction formula is as follows:
in the formulas 1 and 3, R 1 Is a carboxyl protecting group selected from the group consisting of benzyl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, allyl, cyclohexyl, phenyl, 1-naphthyl and 2-naphthyl,
the process comprising reacting a compound of formula 1 or a salt thereof with a compound of formula 2 or a salt thereof in an organic solvent in the presence of an organic base and a condensing agent to produce a compound of formula 3, characterized in that: the condensing agent is selected from the group consisting of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride (DMTMM) and its hydrate, 4- (4, 6-dimethoxy-triazin-2-yl) -4-methylmorpholine tetrafluoroborate and its hydrate, 2,4, 6-trichloro-1, 3, 5-triazine, 2-methoxy-4, 6-dichloro-1, 3, 5-triazine, 4,6, -dibenzyloxy-2-chloro-1, 3, 5-triazine and 4,6, -diphenoxy-2-chloro-1, 3, 5-triazine.
Preferably, the above-mentioned preparation method of the present invention, according to the preparation method of claim 1, the carboxyl protecting group R 1 Is benzyl or methyl, and the salts of the compounds of formula 1 and 2 are each independently selected from the group consisting of hydrochloride, trifluoroacetate, sulfate and sulfonate, preferably hydrochloride or trifluoroacetate.
Preferably, in the above-mentioned preparation method of the present invention, the molar ratio of the condensing agent to the compound of formula 1 is (1.0 to 3.0): 1, preferably (1.1 to 2.0): 1; the condensing agent is preferably 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT) or 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride (DMTMM) and hydrates thereof.
Preferably, in the above preparation method of the present invention, the organic base is triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine (NMM), N-methylcyclohexylamine, N-dimethylaminopyridine or pyridine, preferably N-methylmorpholine (NMM); the molar ratio of the organic base to the compound of formula 1 is at least 1.01:1, preferably (2-10): 1.
Preferably, the above preparation method of the present invention, the organic solvent is selected from one or more of dichloromethane, ethyl acetate, acetonitrile and N, N-Dimethylformamide (DMF), preferably dichloromethane, ethyl acetate, acetonitrile or N, N-Dimethylformamide (DMF), more preferably N, N-Dimethylformamide (DMF); the volume amount of the organic solvent is 0.1-50 times ml/g, preferably 5-20 times ml/g, of the mass of the compound of formula 1.
Preferably, in the preparation method of the invention, the condensation reaction is carried out at a reaction temperature of-10 to 30 ℃, preferably 0 to 25 ℃. The reaction time is 1 to 8 hours, preferably 1 to 4 hours.
In the above-described production method of the present invention, the molar ratio of the condensing agent to the compound of formula 1 is at least 1.01:1, preferably (1.1 to 2.0): 1.
In another embodiment, the present invention also provides a method of preparing carfilzomib comprising:
1) The compound of formula 3 is prepared according to the preparation method of the invention described above;
2) Removing carboxyl protecting groups from the compound of the formula 3 prepared in the previous step to obtain a compound of the formula 4;
3) Reacting a compound of formula 4 with a compound of formula 5 to obtain carfilzomib,
。
the above method for preparing carfilzomib, steps 2) and 3) can be completed by referring to the method described in CN102286070B, and the whole is incorporated by reference, and will not be described in detail.
The invention has the technical effects that: the method for preparing the carfilzomib intermediate compound of the formula 3 takes cheap CDMT and DMTMM as condensing agents, has high reaction yield and purity, simple post-treatment, less three wastes and low cost, and is suitable for large-scale industrial production.
Detailed Description
The following examples are merely representative to aid in understanding and explaining the nature of the invention and are not intended to limit the scope of the invention in any way.
Example 1
30.72g of 4-morpholinoacetic acid, 20.52g of CDMT and 300ml of DMF are added into a reaction bottle, stirred and cooled to 0-15 ℃, 42.91g of NMM is added dropwise, the mixture is stirred for 1 hour under heat preservation, 60.00g of ((S) -2-amino-4-phenylbutyryl) -L-leucyl-L-phenylalanine benzyl ester hydrochloride is added, and the mixture is reacted for 1.5 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-10 ℃, dripping the reaction liquid into 1500ml of water, crystallizing, filtering, decompressing and drying to obtain 62.30g of white solid, wherein the yield is 89.50%, and the chromatographic purity is 99.81%.
Example 2
11.54g of 4-morpholinoacetic acid, 9.30g of CDMT and 300ml of DMF are added into a reaction bottle, stirred and cooled to 0-10 ℃, 26.80g of NMM is added dropwise, the mixture is stirred for 1 hour under heat preservation, 15.00g of ((S) -2-amino-4-phenylbutyryl) -L-leucyl-L-phenylalanine benzyl ester hydrochloride is added, and the mixture is reacted for 4 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-10 ℃, dripping the reaction liquid into 1500ml of water, crystallizing, filtering, decompressing and drying to obtain 15.25g of white solid, wherein the yield is 87.63%, and the chromatographic purity is 99.59%.
Example 3
6.42g of 4-morpholinoacetic acid hydrochloride, 4.02g of CDMT, 10.00g of (S) -2-amino-4-phenylbutyryl) -L-leucyl-L-phenylalanine benzyl ester hydrochloride and 200ml of DMF are added into a reaction bottle, the temperature is controlled to be 15-25 ℃, 4.02g of NMM is added dropwise, and the reaction is carried out for 4 hours under the heat preservation. After the reaction, controlling the temperature to be 0-10 ℃, adding the reaction liquid into 1000ml of water, crystallizing and filtering to obtain 10.25g of white solid, wherein the yield is 90.77%, and the chromatographic purity is 99.73%.
Example 4
5.50g of 4-morpholinoacetic acid, 5.38g of DMTMM and 100ml of DMF are added into a reaction bottle, stirred and cooled to 0-10 ℃, 3.57g of NMM is added dropwise, the mixture is stirred for 1 hour under heat preservation, 10.00g of ((S) -2-amino-4-phenylbutyryl) -L-leucyl-L-phenylalanine benzyl ester hydrochloride is added, and the mixture is reacted for 2 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-10 ℃, dripping the reaction liquid into 500ml of water, crystallizing, filtering, decompressing and drying to obtain 10.39g of white solid, wherein the yield is 89.55%, and the chromatographic purity is 99.84%.
Example 5
10.28g of 4-morpholinoacetic acid, 12.76g of DMTMM and 200ml of DMF are added into a reaction bottle, stirred and cooled to 0-10 ℃, 10.75g of NMM is added dropwise, the mixture is stirred for 1 hour under heat preservation, 20.05g of ((S) -2-amino-4-phenylbutyryl) -L-leucyl-L-phenylalanine benzyl ester hydrochloride is added, and the mixture is reacted for 1.5 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-10 ℃, dripping the reaction liquid into 1000ml of water, crystallizing, filtering, decompressing and drying to obtain 19.92g of white solid, wherein the yield is 85.63%, and the chromatographic purity is 99.79%.
Example 6
16.25g of 4-morpholinoacetic acid trifluoroacetate, 6.30g of CDMT and 200ml of DMF are added into a reaction bottle, stirred and cooled to 5-10 ℃, 11.05g of NMM is added dropwise, the mixture is stirred for 1 hour under heat preservation, 20.10g of ((S) -2-amino-4-phenylbutyryl) -L-leucyl-L-phenylalanine benzyl trifluoroacetate is added, and the mixture is reacted for 2 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-10 ℃, dripping the reaction liquid into 1000ml of water, crystallizing, filtering, decompressing and drying to obtain 18.33g of white solid, wherein the yield is 89.37%, and the chromatographic purity is 99.63%.
Example 7
2.96g of 4-morpholinoacetic acid, 2.15g of CDMT and 40ml of DMF are added into a reaction bottle, stirred and cooled to 5-10 ℃, 4.15g of NMM is added dropwise, the mixture is stirred for 1 hour under heat preservation, 5.00g of ((S) -2-amino-4-phenylbutyryl) -L-leucyl-L-phenylalanine methyl ester hydrochloride is added, and the mixture is reacted for 2 hours under heat preservation. After the reaction is finished, controlling the temperature to be 0-10 ℃, dripping the reaction liquid into 200ml of water, crystallizing, filtering, decompressing and drying to obtain 4.90g of white solid, wherein the yield is 82.70%, and the chromatographic purity is 99.75%.
The above embodiments are exemplary, and any simple modification or variation substantially within the spirit of the present invention is also included in the scope of the present invention.
Claims (10)
1. A method for preparing a compound of a carfilzomib intermediate formula 3, which has the following reaction formula:
in the formulas 1 and 3, R 1 Is a carboxyl protecting group selected from the group consisting of benzyl, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, allyl, cyclohexyl, phenyl, 1-naphthyl and 2-naphthyl,
the process comprising reacting a compound of formula 1 or a salt thereof with a compound of formula 2 or a salt thereof in an organic solvent in the presence of an organic base and a condensing agent to produce a compound of formula 3, characterized in that: the condensing agent is selected from the group consisting of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine, 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride and hydrates thereof, 4- (4, 6-dimethoxy-triazin-2-yl) -4-methylmorpholine tetrafluoroborate and hydrates thereof, 2,4, 6-trichloro-1, 3, 5-triazine, 2-methoxy-4, 6-dichloro-1, 3, 5-triazine, 4,6, -dibenzyloxy-2-chloro-1, 3, 5-triazine and 4,6, -diphenoxy-2-chloro-1, 3, 5-triazine.
2. The process according to claim 1, wherein the carboxyl protecting group R 1 Is benzyl or methyl.
3. The preparation method according to claim 1, wherein the salt is selected from the group consisting of hydrochloride, trifluoroacetate, sulfate and sulfonate, preferably hydrochloride or trifluoroacetate.
4. The process according to claim 1, wherein the molar ratio of the condensing agent to the compound of formula 1 is (1.0 to 3.0): 1, preferably (1.1 to 2.0): 1.
5. The process according to claim 1, wherein the condensing agent is 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine or 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine hydrochloride or a hydrate thereof.
6. The process according to claim 1, wherein the organic base is triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, N-methylcyclohexylamine, N-dimethylaminopyridine or pyridine, preferably N-methylmorpholine.
7. The preparation method according to claim 1, wherein the organic solvent is selected from one or more of dichloromethane, ethyl acetate, acetonitrile and N, N-dimethylformamide, preferably N, N-dimethylformamide.
8. The preparation method according to claim 1, wherein the condensation reaction temperature is-10 to 30 ℃, preferably 0 to 25 ℃.
9. The preparation method according to claim 1, wherein the time of the condensation reaction is 1 to 8 hours, preferably 1 to 4 hours.
10. A method of preparing carfilzomib, comprising:
1) A compound of formula 3 prepared according to the preparation process of any one of claims 1-9;
2) Removing the protecting group from the compound of the formula 3 prepared in the previous step to obtain a compound of the formula 4;
3) Reacting a compound of formula 4 with a compound of formula 5 to obtain carfilzomib,
。
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| CN202310746513.6A CN116768972A (en) | 2023-06-25 | 2023-06-25 | Preparation method of carfilzomib intermediate |
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| CN202310746513.6A CN116768972A (en) | 2023-06-25 | 2023-06-25 | Preparation method of carfilzomib intermediate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286070A (en) * | 2004-08-06 | 2011-12-21 | 普罗特奥里克斯公司 | Compounds for enzyme inhibition |
| CN105143212A (en) * | 2013-03-14 | 2015-12-09 | 欧尼斯治疗公司 | Tripeptide epoxy ketone protease inhibitors |
| US20190085026A1 (en) * | 2015-05-21 | 2019-03-21 | Laurus Labs Private Limited | An improved processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
| CN110964085A (en) * | 2018-09-28 | 2020-04-07 | 扬子江药业集团有限公司 | Preparation method of carfilzomib and derivatives thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286070A (en) * | 2004-08-06 | 2011-12-21 | 普罗特奥里克斯公司 | Compounds for enzyme inhibition |
| CN105143212A (en) * | 2013-03-14 | 2015-12-09 | 欧尼斯治疗公司 | Tripeptide epoxy ketone protease inhibitors |
| US20190085026A1 (en) * | 2015-05-21 | 2019-03-21 | Laurus Labs Private Limited | An improved processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
| CN110964085A (en) * | 2018-09-28 | 2020-04-07 | 扬子江药业集团有限公司 | Preparation method of carfilzomib and derivatives thereof |
Non-Patent Citations (1)
| Title |
|---|
| JINHUA YANG等: "Active ester-based peptide bond formation and its application in peptide synthesis", ORG. CHEM. FRONT., vol. 10, no. 7, 7 April 2023 (2023-04-07), pages 1830 - 1831 * |
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