CN116655601A - Synthesis method of octreotide - Google Patents
Synthesis method of octreotide Download PDFInfo
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- CN116655601A CN116655601A CN202310654862.5A CN202310654862A CN116655601A CN 116655601 A CN116655601 A CN 116655601A CN 202310654862 A CN202310654862 A CN 202310654862A CN 116655601 A CN116655601 A CN 116655601A
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- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 title claims abstract description 23
- 108010016076 Octreotide Proteins 0.000 title claims abstract description 23
- 229960002700 octreotide Drugs 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 238000011534 incubation Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 19
- 230000002194 synthesizing effect Effects 0.000 abstract description 9
- 239000006227 byproduct Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 32
- 239000000203 mixture Substances 0.000 description 4
- PLUKVDOZEJBBIS-UHFFFAOYSA-N N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide Chemical compound C(C=C)(=O)NC1=C(C=C(C(=C1)NC1=NC=CC(=N1)C1=C2N(C3=CC=CC=C13)CCCC2)OC)N(C)CCN(C)C PLUKVDOZEJBBIS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- WRAQQYDMVSCOTE-UHFFFAOYSA-N phenyl prop-2-enoate Chemical compound C=CC(=O)OC1=CC=CC=C1 WRAQQYDMVSCOTE-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention belongs to the technical field of synthesis of medical compounds, and particularly discloses a synthesis method of octreotide. The synthesis method of the invention is to prepare the product of the octreotide by mixing the intermediate 1, the intermediate 2 and the solvent, adding alkali, and heating for reaction. The method for synthesizing the octreotide provided by the invention has the advantages of less byproducts generated in the reaction, high product yield of the octreotide, mild reaction conditions and suitability for industrial scale-up production.
Description
Technical Field
The invention relates to the technical field of synthesis of medical compounds, in particular to a method for synthesizing octreotide.
Background
Ornitinib (structural formula is shown as formula I) is the best third generation EGFR inhibitor in global sales at present, and is mainly used for treating non-small cell lung cancer.
At present, a Guan Aoxi tenib synthesis method is reported more, but the reported synthesis method basically uses the following intermediate 1 to react with acryloyl chloride or 3-chloropropionyl chloride to prepare the octenib.
In the actual preparation of the octreotide, the method of reacting the intermediate 1 with the acryloyl chloride is found, because the stability of the acryloyl chloride is poor, polymerization impurities are easy to generate, and other impurities are easy to generate with the intermediate 1, so that the separation and purification of the product are difficult, the purity of the product is low, and the yield is also influenced. By adopting the method of reacting the intermediate 1 with 3-chloropropionyl chloride, two molecular products (shown as a formula II) are easy to generate, and the problems of difficult separation and purification of the products, low product purity, low yield and the like are also existed.
Aiming at the problems existing in the prior art when the oritinib is prepared, a new synthesis method is necessary to be developed, and the method has important significance for realizing the industrial production of the oritinib.
Disclosure of Invention
The invention mainly solves the technical problem of providing the method for synthesizing the octreotide, which can reduce the generation of byproducts and improve the yield of products.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthesis method of octreotide, wherein the reaction equation of the synthesis method is as follows:
wherein the substituent R in intermediate 2 1 Represents H, -CN or-NO 2 ；
The synthesis method comprises the following steps: and mixing the intermediate 1, the intermediate 2 and the solvent, adding alkali, and heating to react to obtain the product of the octreotide.
As one embodiment of the present invention, the substituent R in the intermediate 2 1 represents-CN or-NO 2 。
Preferably, the substituent R in said intermediate 2 1 represents-NO 2 。
As an embodiment of the present invention, the solvent is at least one selected from tetrahydrofuran, ethyl acetate, acetonitrile, N-dimethylformamide.
Preferably, the solvent is selected from ethyl acetate and/or acetonitrile.
As an embodiment of the present invention, the base is selected from any one of triethylamine, sodium bicarbonate, sodium carbonate, and potassium carbonate.
Preferably, the base is sodium bicarbonate.
As an embodiment of the invention, the base is added in portions.
As an embodiment of the present invention, the temperature-increasing reaction includes: heating to 20-50 deg.c, and maintaining the temperature to react.
Preferably, the temperature-increasing reaction includes: heating to 38-42 deg.c, and maintaining the temperature to react.
As one embodiment of the present invention, the molar ratio of the intermediate 1 to the intermediate 2 is 1: (1 to 1.5), preferably 1: (1.2 to 1.5), more preferably 1:1.2.
as one embodiment of the present invention, the molar ratio of the intermediate 1 to the base is 1: (1 to 1.5), preferably 1:1.2.
as one embodiment of the invention, the method for synthesizing the octreotide provided by the invention comprises the following steps:
firstly, adding the intermediate 1 into a solvent to obtain a reaction liquid 1;
adding a mixed solution of the intermediate 2 and the solvent into the reaction solution 1 under stirring to obtain a reaction solution 2;
and (3) adding the alkali into the reaction liquid 2 in batches, controlling the temperature of a reaction system to be less than or equal to 20 ℃ in the feeding process, heating the reaction system after the alkali is added, and then carrying out heat preservation for reaction to obtain the product of the octreotide.
As one embodiment of the present invention, the incubation time is 10 to 18 hours, preferably 10 to 15 hours.
The method for synthesizing the octreotide provided by the invention has the advantages of less byproducts generated by the reaction, high product yield of the octreotide, low toxicity of raw materials, mild reaction conditions and suitability for industrial scale-up production.
Detailed Description
The following describes the technical scheme of the present invention in detail by examples.
The raw materials used in the following examples, not specifically described, were all obtained by purchase.
Example 1
The embodiment provides a synthesis method of the oritinib, wherein the reaction equation is as follows:
specifically, in this embodiment, substituent R on intermediate 2 1 And represents H, namely the intermediate 2 is phenyl acrylate, and the structural formula is as follows:
the synthesis method comprises the following steps:
445g of intermediate 1 was added to 2L of tetrahydrofuran solvent to obtain reaction liquid 1;
177.6g of intermediate 2 (1.2 eq) was diluted with 1L of tetrahydrofuran solvent to give a mixture of intermediate 2 and tetrahydrofuran solvent;
then adding the prepared mixed solution of the intermediate 2 and tetrahydrofuran solvent into the reaction solution 1 under stirring to obtain a reaction solution 2;
then 121.2g (1.2 eq) of triethylamine is added into the reaction liquid 2 in batches, and the temperature of the reaction system is controlled to be not more than 20 ℃ in the feeding process; after the triethylamine is added, the reaction system is heated, the temperature is kept for reaction for 12 hours after the triethylamine is heated to 40 ℃, the disappearance of the raw material intermediate 1 is monitored, and the reaction is finished.
The reaction is post-treated, the solvent is removed by rotary evaporation, the rotary evaporation residue is cooled to below 5 ℃, 1mol/L of dilute hydrochloric acid solution 1.5L is slowly added, the mixture is stirred for 30 minutes after the addition, the mixture is extracted for 2 times by ethyl acetate, the rest water phase is cooled to about 0 ℃, 1.5L of sodium hydroxide aqueous solution 1mol/L is slowly added at the moment, and then the mixture is stirred and crystallized for 5 hours at the temperature of 0 ℃ to obtain 224.5g of solid of the Ornitinib, and the yield is 45.0%. The product HPLC purity was 99.1%.
Examples 2 to 3
Examples 2 and 3 each provide a synthetic method of octreotide, mainly examining the effect on the reaction by using different intermediates 2.
Examples 2 and 3 differ from example 1 only in the intermediate 2 employed, all other conditions being identical.
The structural formula of intermediate 2 used in examples 2 and 3 and the experimental results are shown in table 1.
TABLE 1
As can be seen from the above table, substituent R in intermediate 2 1 is-NO 2 In this case, the yield of the product is remarkably improved. Thus, the substituent R in intermediate 2 is preferred 1 represents-NO 2 Next is substituent R in intermediate 2 1 represents-CN.
Examples 4 to 6
Examples 4-6 provide a method for synthesizing octenib, respectively, and mainly examine the effect of using different bases on the reaction.
Examples 4 to 6 differ from example 2 only in the base used and the other conditions are the same.
The bases used in examples 4-6 and the experimental results are shown in Table 2.
TABLE 2
As can be seen from the above table, when the base used is sodium bicarbonate, the yield of the product is highest and can reach more than 90% under the same conditions. The base is therefore preferably sodium bicarbonate.
Examples 7 to 9
Examples 7-9 provide a method for synthesizing octreotide, respectively, and mainly examine the influence of different solvents on the reaction.
Examples 7 to 9 differ from example 4 only in the solvents used, all other conditions being identical.
The solvents used in examples 7-9 and the experimental results are shown in Table 3.
TABLE 3 Table 3
As can be seen from the table, when acetonitrile or ethyl acetate is adopted as the solvent, the yield of the product is improved by 93.6% at most under the same conditions as that of tetrahydrofuran solvent. Thus acetonitrile or ethyl acetate is preferably used as the reaction solvent.
Examples 10 to 11
Examples 10-11 provide a method for synthesizing octreotide, respectively, and mainly examine the influence of different reaction temperatures on the reaction.
Examples 10 to 11 differ from example 7 only in the reaction temperature, and all other conditions are the same.
The reaction temperatures and experimental results used in examples 10-11 are shown in Table 4.
TABLE 4 Table 4
As can be seen from the above table, the reaction temperature has a certain influence on the yield of the reaction product, and the reaction temperature is preferably in the range of 25 to 40℃and more preferably around 40 ℃.
Examples 12 to 13
Examples 12-13 provide a method for synthesizing octreotide, respectively, and mainly examine the influence of different feeding equivalents of the intermediate 2 on the reaction.
Examples 12-13 differ from example 7 only in the equivalent charge of intermediate 2, all other conditions being identical.
The feed equivalent weights and experimental results used in examples 12-13 are shown in Table 5.
TABLE 5
As can be seen from the above table, the amount of intermediate 2 fed is preferably: the feeding mole ratio of the intermediate 1 to the intermediate 2 is 1: (1.2 to 1.5), more preferably 1:1.2.
according to the above examples, the synthesis method of the invention can successfully prepare the target product of the Ornitinib. In particular, under specific conditions, for example, by specific preference of the reactants, the reaction solvent, the reaction temperature, the amount of the fed materials, etc., the objective product can be obtained in high yield.
Through detection, the HPLC purity of the obtained octreotide products in the examples 1-13 is between 99.0% and 99.5%, and the product purity is high.
The foregoing description is only illustrative of the present invention and is not intended to limit the scope of the invention, and all equivalent modifications made by the teachings of the present invention, or direct or indirect application in other related arts, are included in the scope of the present invention.
Claims (10)
1. The synthesis method of the octreotide is characterized in that the reaction equation of the synthesis method is as follows:
wherein R is 1 Represents H, -CN or-NO 2 ；
The synthesis method comprises the following steps: and mixing the intermediate 1, the intermediate 2 and the solvent, adding alkali, and heating to react to obtain the product of the octreotide.
2. The synthetic method according to claim 1, wherein the substituent R in the intermediate 2 1 represents-CN or-NO 2 Preferably, the substituent R in the intermediate 2 1 represents-NO 2 。
3. The synthetic method according to claim 1 or 2, wherein the solvent is at least one selected from tetrahydrofuran, ethyl acetate, acetonitrile, N-dimethylformamide; preferably, the solvent is selected from ethyl acetate and/or acetonitrile.
4. A synthetic method according to claim 3, characterized in that the base is selected from any of triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, preferably the base is sodium bicarbonate.
5. The method of synthesis according to claim 4, wherein the base is added in portions.
6. The synthetic method of any one of claims 1 to 5 wherein the elevated temperature reaction comprises: heating to 20-50 ℃, and then preserving heat for reaction; preferably, the reaction is carried out by heating to 38-42 ℃ and then preserving heat.
7. The synthesis method according to claim 6, wherein the molar ratio of the intermediate 1 to the intermediate 2 is 1: (1 to 1.5), preferably 1: (1.2 to 1.5), more preferably 1:1.2.
8. the synthesis method according to claim 7, wherein the molar ratio of the intermediate 1 to the base is 1: (1 to 1.5), preferably 1:1.2.
9. the synthetic method according to any one of claims 1 to 8, characterized in that it comprises the steps of:
firstly, adding the intermediate 1 into a solvent to obtain a reaction liquid 1;
adding a mixed solution of the intermediate 2 and the solvent into the reaction solution 1 under stirring to obtain a reaction solution 2;
and (3) adding the alkali into the reaction liquid 2 in batches, controlling the temperature of a reaction system to be less than or equal to 20 ℃ in the feeding process, heating the reaction system after the alkali is added, and then carrying out heat preservation for reaction to obtain the product of the octreotide.
10. The synthesis according to claim 9, wherein the incubation time is 10 to 18 hours, preferably 10 to 15 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310654862.5A CN116655601A (en) | 2023-06-05 | 2023-06-05 | Synthesis method of octreotide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310654862.5A CN116655601A (en) | 2023-06-05 | 2023-06-05 | Synthesis method of octreotide |
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| Publication Number | Publication Date |
|---|---|
| CN116655601A true CN116655601A (en) | 2023-08-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310654862.5A Pending CN116655601A (en) | 2023-06-05 | 2023-06-05 | Synthesis method of octreotide |
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| Country | Link |
|---|---|
| CN (1) | CN116655601A (en) |
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2023
- 2023-06-05 CN CN202310654862.5A patent/CN116655601A/en active Pending
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