CN117736211A - Synthetic method of rebaudinib intermediate - Google Patents
Synthetic method of rebaudinib intermediate Download PDFInfo
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- CN117736211A CN117736211A CN202311796746.3A CN202311796746A CN117736211A CN 117736211 A CN117736211 A CN 117736211A CN 202311796746 A CN202311796746 A CN 202311796746A CN 117736211 A CN117736211 A CN 117736211A
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- 238000010189 synthetic method Methods 0.000 title description 3
- 229940126214 compound 3 Drugs 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 17
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000001308 synthesis method Methods 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000001514 detection method Methods 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 238000004321 preservation Methods 0.000 claims description 8
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 6
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 claims description 4
- 238000010009 beating Methods 0.000 claims description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 abstract description 10
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 abstract description 3
- 239000012452 mother liquor Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- LXCZVGKSFJMLRO-UHFFFAOYSA-N 2-chloro-7-cyclopentylpyrrolo[2,3-d]pyrimidine-6-carboxylic acid Chemical compound OC(=O)C1=CC2=CN=C(Cl)N=C2N1C1CCCC1 LXCZVGKSFJMLRO-UHFFFAOYSA-N 0.000 description 4
- ADHCEFBFOBDYEC-UHFFFAOYSA-N (2-chloro-7-cyclopentylpyrrolo[2,3-d]pyrimidin-6-yl)methanol Chemical compound OCC1=CC2=CN=C(Cl)N=C2N1C1CCCC1 ADHCEFBFOBDYEC-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- SOXVKQLLJZHYTL-UHFFFAOYSA-N 2-chloro-7-cyclopentylpyrrolo[2,3-d]pyrimidine-6-carbaldehyde Chemical compound C12=NC(Cl)=NC=C2C=C(C=O)N1C1CCCC1 SOXVKQLLJZHYTL-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
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- 238000001727 in vivo Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
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- CHGKAGOTEWCHJL-UHFFFAOYSA-N 3-[2-chloro-4-(cyclopentylamino)pyrimidin-5-yl]prop-2-yn-1-ol Chemical compound OCC#CC1=CN=C(Cl)N=C1NC1CCCC1 CHGKAGOTEWCHJL-UHFFFAOYSA-N 0.000 description 1
- SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical compound ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a synthesis method of a rebaudinib intermediate, and belongs to the technical field of drug synthesis. The preparation route is as follows:the method comprises the steps of carrying out a first treatment on the surface of the The synthesis method comprises the following steps: compound 1 was directly oxidized to compound 3 by IBD and TEMPO one-pot process in one step. The invention adopts a one-pot method to directly oxidize the hydroxyl of the compound 1 into carboxylic acid to obtain a compound 3; the scheme has the advantages that the high-purity compound 3 can be directly obtained in one step through the reaction, the yield reaches 95%, and the mother liquor can be purified to obtain the byproduct iodobenzene.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing a rebaudinib intermediate.
Background
Rabociclib (CAS: 1256963-02-6) is a CDK4/6 protein kinase inhibitor developed by North corporation that binds to cyclin, promotes phase transition of the cell cycle, initiates DNA synthesis, and regulates cell transcription. The CDK4/6 inhibitor can block tumor cells in the first stage of the cell cycle, thereby inhibiting tumor proliferation. The FDA approved 3 month in 2017 for the treatment of breast cancer. Preclinical routine liver microsome incubation of major metabolites M4 and M15, preclinical rat and canine in vivo ADME studies found that the drug was widely metabolized in vivo, with the highest metabolite in plasma being M13, with a rat AUC plasma M13 of 38%.
The intermediate 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid is one of key intermediates for synthesizing Rabociclib, and has the following structure:
。
the patent application No. 202311110841.3 discloses a method for synthesizing the above intermediate, which adopts 5-bromo-2, 4-dichloropyrimidine as a starting material, firstly reacts to generate 5-bromo-2-chloro-N-cyclopentyl pyrimidine-4 amine, and then is coupled with propynyl alcohol by palladium catalysis to obtain 3- (2-chloro-4-cyclopentylamino-pyrimidin-5-yl) -prop-2-yn-1-ol; then intramolecular cyclization is carried out to generate the (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-yl) -methanol. (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidin-6-yl) -methanol is oxidized twice, the alcoholic hydroxyl is oxidized into aldehyde group by manganese dioxide to obtain 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formaldehyde, and then the aldehyde group is oxidized into carboxyl by potassium hydrogen persulfate to obtain 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid. Therefore, the existing synthesis method needs to perform two-step synthesis when preparing 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid, and has the problems of low reaction yield, complex operation and the like because the components of a reaction product are complex when preparing 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-formaldehyde and purifying by adopting a column chromatography mode.
Disclosure of Invention
Aiming at the problems of complex oxidation steps, low product yield and the like in the prior art when the rebaudinib intermediate is synthesized, the invention provides a synthesis method of the rebaudinib intermediate. The invention adopts a one-step method to directly oxidize (2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-yl) -methanol to synthesize 2-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid, the purity of the obtained product is high, the post-treatment is simple and convenient, the product yield is high, and the filtered mother liquor can be purified to obtain the byproduct iodobenzene.
The technical scheme of the invention is as follows:
a synthetic method of a Rabociclib intermediate comprises the following preparation routes:
；
the method comprises the following steps:
compound 1 was directly oxidized to compound 3 by IBD (iodobenzene diacetic acid) and TEMPO (2, 6-tetramethylpiperidine oxide) in one step.
Further, compound 3 also includes a purification process by beating with acetic acid.
Further, the specific method is as follows:
acetonitrile, tetrahydrofuran and water I are added into the compound 1, the temperature is controlled to be 20-30 ℃, cyclohexene and TEMPO are added under stirring, IBD is added in batches, and after the heat preservation reaction is carried out for 10 hours at 20-30 ℃, the compound 2/compound 3 is detected to be less than or equal to 1.0%; and (3) adding water II after the detection is qualified, stirring, crystallizing, filtering, and drying to obtain the compound 3.
Furthermore, the amount of cyclohexene is 1 to 1.1mol/mol based on the amount of the compound 1.
Furthermore, the dosage of TEMPO is 0.1-0.2 mol/mol based on the amount of the compound 1.
Further, the IBD dose is 2.0-2.5 mol/mol based on the compound 1 feed.
Furthermore, the dosage of acetonitrile is 6-8 mL/g according to the dosage of the compound 1; the dosage of tetrahydrofuran is 1-2 mL/g; the dosage of the water I is 0.5-1 mL/g; the dosage of the water II is 2-3 mL/g.
The invention has the beneficial effects that:
the invention adopts a one-pot method to directly oxidize the hydroxyl of the compound 1 into carboxylic acid to obtain a compound 3; the scheme has the advantages that the high-purity compound 3 can be directly obtained in one step through the reaction, the yield reaches 95%, and the mother liquor can be purified to obtain the byproduct iodobenzene.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the description of the embodiments or the prior art will be briefly described below, and it will be obvious to those skilled in the art that other drawings can be obtained from these drawings without inventive effort.
FIG. 1 is an HPLC chart of preparation of Compound 3 of example 1 of the present invention.
FIG. 2 is an HPLC chart of preparation of Compound 3 of example 2 of the present invention.
FIG. 3 is an HPLC chart of preparation of Compound 3 of example 3 of the present invention.
FIG. 4 is an HPLC chart of preparation of Compound 3 of example 4 of the present invention.
FIG. 5 is an HPLC chart of preparation of Compound 3 of example 5 of the present invention.
FIG. 6 is an HPLC chart of preparation of compound 3 of example 6 of the present invention.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
Example 1
Adding 490L acetonitrile, 70L tetrahydrofuran and 35L water into 70kg of compound 1, controlling the temperature at 20-30 ℃, adding 22.84kg cyclohexene and 4.35kg TEMPO under stirring, then adding 197.06kg IBD,20~30 ℃ in batches, and carrying out heat preservation reaction for 10 hours, and detecting that the compound 2/compound 3 is less than or equal to 1.0%; after the detection is qualified, 140L of water is added, stirring crystallization is carried out, filtration is carried out, 140kg of acetic acid is added into a filter cake for pulping, 70.20kg of compound 3 is obtained after suction filtration and drying, the yield is 95.0%, the HPLC diagram is shown in figure 1, and the detection result is as follows:
table 1 example 1 product HPLC assay results
Example 2
Adding 490L acetonitrile, 70L tetrahydrofuran and 35L water into 70kg of compound 1, controlling the temperature at 20-30 ℃, adding 22.90kg cyclohexene and 4.40kg TEMPO under stirring, then adding 198.00kg IBD,20~30 ℃ in batches, and carrying out heat preservation reaction for 10 hours, and detecting that the compound 2/compound 3 is less than or equal to 1.0%; after the detection is qualified, 140L of water is added, stirring crystallization is carried out, filtration is carried out, 140kg of acetic acid is added into a filter cake for pulping, the compound 3.56 kg is obtained after suction filtration and drying, the yield is 95.5%, the HPLC diagram is shown in figure 2, and the detection result is as follows:
TABLE 2 HPLC detection results for example 2 product
Example 3
Adding 490L acetonitrile, 70L tetrahydrofuran and 35L water into 70kg of compound 1, controlling the temperature at 20-30 ℃, adding 22.90kg cyclohexene and 4.45kg TEMPO under stirring, then adding 198.46kg IBD,20~30 ℃ in batches, and carrying out heat preservation reaction for 10 hours, and detecting that the compound 2/compound 3 is less than or equal to 1.0%; after the detection is qualified, 140L of water is added, stirring crystallization is carried out, filtration is carried out, 140kg of acetic acid is added into a filter cake for pulping, the compound 3.12 kg is obtained after suction filtration and drying, the yield is 94.9%, the HPLC diagram is shown in figure 3, and the detection result is as follows:
TABLE 3 HPLC detection results for example 3 product
Example 4
Adding 490L acetonitrile, 70L tetrahydrofuran and 35L water into 70kg of compound 1, controlling the temperature at 20-30 ℃, adding 22.88kg cyclohexene and 4.35kg TEMPO under stirring, then adding 197.08kg IBD,20~30 ℃ in batches, and carrying out heat preservation reaction for 10 hours, and detecting that the compound 2/compound 3 is less than or equal to 1.0%; after the detection is qualified, 140L of water is added, stirring crystallization is carried out, filtration is carried out, 140kg of acetic acid is added into a filter cake for pulping, 70.20kg of compound 3 is obtained after suction filtration and drying, the yield is 95.9%, the HPLC diagram is shown in figure 4, and the detection result is as follows:
TABLE 4 HPLC detection results for example 4 product
Example 5
Adding 735L of acetonitrile, 105L of tetrahydrofuran and 53L of water into 105kg of compound 1, controlling the temperature to be 20-30 ℃, adding 34.30kg of cyclohexene and 6.60kg of TEMPO under stirring, then adding 295.60kg IBD,20~30 ℃ in batches, and reacting for 10 hours under heat preservation, and detecting that the compound 2/compound 3 is less than or equal to 1.0%; after the detection is qualified, 140L of water is added, stirring crystallization is carried out, filtration is carried out, 210kg of acetic acid is added into a filter cake for pulping, the compound 3.85 kg is obtained after suction filtration and drying, the yield is 95.5%, the HPLC diagram is shown in figure 5, and the detection result is as follows:
TABLE 5 HPLC detection results for example 5 product
Example 6
Adding 980L acetonitrile, 140L tetrahydrofuran and 70L water into 140kg of compound 1, controlling the temperature at 20-30 ℃, adding 45.68kg cyclohexene and 8.70kg TEMPO under stirring, then adding 390 kg IBD in batches, and detecting that the compound 2/compound 3 is less than or equal to 1.0% after heat preservation reaction for 10 hours at 20-30 ℃; after the detection is qualified, 140L of water is added, stirring crystallization is carried out, filtration is carried out, 280kg of acetic acid is added into a filter cake for pulping, 141.87kg of compound 3 is obtained after suction filtration and drying, the yield is 96.0%, the HPLC diagram is shown in figure 6, and the detection result is as follows:
TABLE 6 HPLC detection results for example 6 product
Although the present invention has been described in detail by way of preferred embodiments with reference to the accompanying drawings, the present invention is not limited thereto. Various equivalent modifications and substitutions may be made in the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and it is intended that all such modifications and substitutions be within the scope of the present invention/be within the scope of the present invention as defined by the appended claims.
Claims (8)
1. A synthesis method of a rebaudinib intermediate is characterized by comprising the following preparation routes:
；
the method comprises the following steps:
compound 1 is directly oxidized to compound 3 in one step by a one-pot process of iodobenzene diacetic acid and 2, 6-tetramethylpiperidine oxide.
2. The method for synthesizing the rebaudinib intermediate according to claim 1, wherein the compound 3 is obtained and further comprises a process of purifying by beating with acetic acid.
3. The method for synthesizing the rebaudinib intermediate according to claim 1, which is characterized by comprising the following steps:
acetonitrile, tetrahydrofuran and water I are added into a compound 1, the temperature is controlled to be 20-30 ℃, cyclohexene and 2, 6-tetramethylpiperidine oxide are added under stirring, then iodobenzene diacetic acid is added in batches, and the compound 2/compound 3 is detected to be less than or equal to 1.0% after heat preservation reaction is carried out for 10 hours at 20-30 ℃; and (3) adding water II after the detection is qualified, stirring, crystallizing, filtering, and drying to obtain the compound 3.
4. The method for synthesizing a rebaudinib intermediate according to claim 3, wherein the amount of cyclohexene is 1 to 1.1mol/mol based on the amount of the compound 1.
5. The method for synthesizing a rebaudinib intermediate according to claim 3, wherein the amount of 2, 6-tetramethylpiperidine oxide used is 0.1 to 0.2mol/mol based on the amount of the compound 1.
6. The method for synthesizing a rebaudinib intermediate according to claim 3, wherein the amount of iodobenzene diacetic acid is 2.0-2.5 mol/mol based on the amount of the compound 1.
7. The method for synthesizing the rebaudinib intermediate according to claim 3, wherein the amount of acetonitrile is 6-8 mL/g, the amount of tetrahydrofuran is 1-2 mL/g and the amount of water I is 0.5-1 mL/g based on the amount of the compound 1.
8. A method of synthesizing a rebaudinib intermediate according to claim 3, wherein the amount of water ii is 2-3 ml/g.
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| CN202311796746.3A CN117736211A (en) | 2023-12-25 | 2023-12-25 | Synthetic method of rebaudinib intermediate |
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| CN202311796746.3A CN117736211A (en) | 2023-12-25 | 2023-12-25 | Synthetic method of rebaudinib intermediate |
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