CN112062742B - Preparation method of tylosin - Google Patents

Preparation method of tylosin Download PDF

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CN112062742B
CN112062742B CN202011003431.5A CN202011003431A CN112062742B CN 112062742 B CN112062742 B CN 112062742B CN 202011003431 A CN202011003431 A CN 202011003431A CN 112062742 B CN112062742 B CN 112062742B
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compound
temperature
stirring
dropwise adding
tylosin
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CN112062742A (en
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高悦译
卢江
陈成斌
刘恩桂
张倩
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Guangzhou Lixin Pharmaceuticals Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tylosin. The tylosin of the invention is prepared by reacting a compound N-9, N-butyllithium and a compound N-8 to obtain a compound N-10-a, then adding triethylsilane and boron trifluoride diethyl etherate to react to obtain a compound N-11, and then adding Lewis acid to react. The preparation method shortens the synthetic route of the tylosin, and the obtained tylosin has high yield, low impurity content and stable property.

Description

Preparation method of tylosin
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tylosin.
Background
Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defective insulin secretion or impaired insulin action, and prior art drugs are mainly treated based on the source of blood glucose or/and the destination of blood glucose as entry points, e.g., insulin is treated through both entry points simultaneously. But the fact that, in addition to the two mentioned points of entry, the kidney also plays an important role in the regulation of blood glucose, studies have shown that: 180g glucose per day is filtered from the glomerulus, but is completely absorbed back by the tubules, so there is no sugar in the urine and the urine sugar is negative; when the blood sugar concentration exceeds 11mmol/L, too much glucose is filtered out from the glomerulus, and the glucose exceeds the resorption capacity of the renal tubules, so that the glucose is excreted with urine, and the urine glucose is positive. The substance of the renal tubular glucose responsible for sugar resorption is 'sodium-glucose cotransporter 2' (SGLT-2), and the SGLT-2 inhibitor can selectively inhibit SGLT-2, thereby playing roles in reducing weight, causing little hypoglycemia, having treatment effect independent of a hypoglycemic pathway of insulin secretion and the like. SGLT-2 inhibitors include tylagliflozin, dapagliflozin, regagliflozin, sjogrezin, canagliflozin, alogliptin and the like, with the most potent SGLT-2 inhibitor of tylagliflozin currently found providing another strong and effective choice for clinical treatment.
Aiming at the preparation method of the tylagliflozin in the prior art, as disclosed in the chinese patent CN111592515A previously filed by the inventor, the main synthetic route of the preparation method of the SGLT2 inhibitor with the function of reducing blood sugar is roughly shown as the following formula:
Figure BDA0002695098320000021
in the synthetic route, although the first 3 steps can obtain the tylosin with higher yield, the synthetic route is greatly prolonged because anisole and aluminium trichloride debenzylation are adopted in the step 3, and the intermediate 2 easily contains specific impurities due to the effect of gram-binding reaction, so that the acetylation and deacetylation of the step 4 and the step 5 are required to be removed, and finally, the purified product is obtained by further recrystallization.
Disclosure of Invention
The invention aims to provide a preparation method of tylosin, which takes a compound N-10-a as a starting material, prepares the compound N-10-a, then prepares a compound N-11, and then reacts with Lewis acid to obtain the tylosin with high yield and low impurity content.
In order to achieve the purpose, the invention adopts the following technical scheme:
the preparation method of the tylosin comprises the steps of reacting a compound N-9, N-butyllithium and a compound N-8 to obtain a compound N-10-a, adding triethylsilane and boron trifluoride diethyl etherate to react to obtain a compound N-11, and adding Lewis acid to react to obtain the tylosin;
Figure BDA0002695098320000032
compound N-9;
Figure BDA0002695098320000033
compound N-8;
Figure BDA0002695098320000034
N-10-a；
Figure BDA0002695098320000035
compound N-11.
Further, the synthetic route of the tylagliflozin is as follows:
Figure BDA0002695098320000031
further, the preparation method of the tylosin comprises the following steps:
s1) taking the compound N-9 and anhydrous tetrahydrofuran, stirring, replacing with nitrogen for three times, cooling, controlling the temperature to be-80 to-75 ℃, dropwise adding N-hexane solution of N-butyllithium for 1 to 2 hours, and stirring for 1 hour after dropwise adding; continuously controlling the temperature to be-80 to-75 ℃, dropwise adding a tetrahydrofuran solution of a compound N-8 for 1 to 2 hours, and stirring for 1.5 to 3 hours under the condition of heat preservation after the dropwise adding is finished until the TLC monitoring reaction is complete; controlling the temperature to be below-20 ℃, dropwise adding an ammonium chloride aqueous solution, then returning the temperature to 10-15 ℃, extracting with dichloromethane, taking an organic phase, washing with saturated saline, drying, and concentrating under reduced pressure until no fraction is obtained to obtain a compound N-10-a;
s2) diluting and dissolving the compound N-10-a obtained in the step S1 by using dichloromethane, adding triethylsilane, cooling to-30 ℃ under the protection of nitrogen, dropwise adding boron trifluoride diethyl etherate, and keeping the temperature at-20 to-30 ℃ after dropwise adding until the TLC monitoring reaction is complete; controlling the temperature to be below-20 ℃, dropwise adding a saturated sodium bicarbonate solution, stirring for 0.5-1 h, standing, separating liquid, taking an organic phase, washing with saturated brine, drying, concentrating under reduced pressure until no fraction is produced, adding N-heptane, stirring, crystallizing, filtering, and drying to obtain a compound N-11;
s3) mixing and stirring the compound N-11, the compound A and dichloromethane in the step S2 until the compounds are dissolved, cooling, controlling the temperature to be minus 50 ℃ to minus 45 ℃, adding a dichloromethane solution of Lewis acid, and keeping the temperature and stirring for 0.5-1 h after the dropping is finished until the TLC monitoring reaction is complete; controlling the temperature to be below minus 20 ℃, dropwise adding triethylamine to stop the reaction, washing with a saturated sodium bicarbonate solution, washing with purified water, drying, concentrating under reduced pressure until no fraction is produced, adding n-heptane, stirring, crystallizing, filtering, and drying to obtain the product.
Further, in the step S1, the equivalent ratio of the compound N-9 to the N-butyllithium to the compound N-8 is (1-1.5): (1-1.5): 1
Further, the equivalent ratio of the compound N-9, N-butyllithium and the compound N-8 in the step S1 is 1.25: 1.25: 1.
further, the equivalent ratio of the compound N-9 to the triethylsilane to the boron trifluoride diethyl etherate is (1-1.5): (1.5-2): (1-1.5).
Further, the equivalent ratio of the compound N-9, triethylsilane and boron trifluoride diethyl etherate was 1.2: 2: 1.2.
Further, the equivalent ratio of the compound N-11 and the lewis acid in the step S3 is 1: (5-10).
Further, the equivalent ratio of the compound N-11 and the lewis acid in the step S3 is 1: 5.
further, the lewis acid includes boron trichloride, boron trifluoride, and boron tribromide.
Further, the equivalent ratio of compound N-11 to compound a in step S3 is 1: (3-8).
Further, the equivalent ratio of compound N-11 to compound a in step S3 is 1: 4.
further, the structural general formula of the compound A is
Figure BDA0002695098320000041
Wherein R1, R2, R3, R4 and R5 are respectively selected from-H, - (CH)2)nCH3、-O(CH2) nCH3At least one of R1, R2, R3, R4 and R5 are not H at the same time, and n is an integer of 0-10.
Further, the compound A comprises one of trimethylbenzene, 1,2,4, 5-tetramethylbenzene, pentamethylbenzene, anisole, phenetole, 1, 3-dimethoxybenzene and 1, 3-diethoxybenzene.
Further, the equivalent ratio of the compound N-11 to triethylamine in the step S3 is 1: 3.
further, the TLC in step S1 was monitored with petroleum ether: ethyl acetate ═ 6: 1 is used as a developing agent, and the reaction is complete without a compound N-8; the TLC monitoring in step S2 was performed with petroleum ether: ethyl acetate ═ 6: 1 is used as a developing agent, and the reaction is complete without a compound N-10-a; the TLC monitoring in step S3 was performed with petroleum ether: ethyl acetate ═ 6: 1 as developing agent, the reaction is complete without compound N-11.
Further, the drying agent used for drying in the steps S1, S2 and S3 is anhydrous sodium sulfate.
Further, the preparation method of the tylosin further comprises recrystallization, and the recrystallization comprises the following specific steps: and (5) mixing the product obtained in the step (S3) with the mixed solvent, heating to 60 ℃, dissolving and clarifying, carrying out hot filtration, slowly cooling to 25-30 ℃, controlling the cooling time to be 4-6 h, filtering, and drying to obtain the product.
Further, the mixed solvent was prepared from ethyl acetate and n-heptane in a ratio of 2: 1, in terms of mass ratio.
The invention also aims to provide the tylagliflozin prepared by the preparation method.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the invention, a compound N-10-a is taken as an initial raw material, the compound N-10-a is obtained by reacting with N-butyllithium and a compound N-8, then triethylsilane and boron trifluoride diethyl etherate are added for reacting to obtain a compound N-11, and Lewis acid is added for reacting to obtain the tylosin, the synthesis steps are reduced from 5 steps to 3 steps, the synthesis route is greatly shortened, tests show that the yield of the tylosin is high and reaches over 90%, and the yield of the purified tylosin after recrystallization of the tylosin reaches over 80%.
(2) The preparation method provided by the invention avoids the use of aluminum element, the problem that the final product does not need to detect metal residue is solved, the solvent is replaced by dichloromethane from anisole, the anisole has high boiling point and is easy to operate, the difficulty of post-treatment is greatly simplified, and experiments II and III show that the content of known impurities TY702-Bn in the obtained telagliflozin is low, the total impurities are low, and the properties are stable.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1 preparation method of tylosin
The method comprises the following steps:
s1. Compound N-10-a
Figure BDA0002695098320000061
Preparation of
Stirring 112g of compound N-9(0.347mol, 1.25eq) and 720ml of anhydrous tetrahydrofuran, replacing with nitrogen for three times, cooling, controlling the temperature to be-80 to-75 ℃, dropwise adding 240ml of 1.6M N-hexane solution (0.347mol, 1.25eq) of N-butyllithium for 2h, and stirring for 1h under heat preservation after dropwise adding; continuously controlling the temperature to be-80 to-75 ℃, dropwise adding a tetrahydrofuran solution of a compound N-8 (120g of the compound N-8(0.277mol, 1.0eq) is dissolved in 240ml of tetrahydrofuran), wherein the dropwise adding time is 2h, and after the dropwise adding is finished, keeping the temperature and stirring for 2h until the TLC monitoring reaction is complete (the reaction is complete when no compound N-8 exists and petroleum ether: ethyl acetate is 6: 1 is used as a developing agent); controlling the temperature to be below minus 20 ℃, dropwise adding 600ml of 10 wt% ammonium chloride aqueous solution, then returning the temperature to 10 ℃, extracting with 1600ml of dichloromethane, taking an organic phase, washing with 1500ml of saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure until no fraction is obtained, obtaining 250g of a compound N-10-a, and continuously feeding the compound N-10-a into the step S2 according to 100% yield.
S2. Compound N-11
Figure BDA0002695098320000062
Preparation of
Diluting and dissolving 250g of the compound N-10-a obtained in the step S1 with 1200ml of dichloromethane, adding 64.4g of triethylsilane (0.554mol, 2.0eq), cooling to-30 to-20 ℃ under the protection of nitrogen, dropwise adding 47.2g of boron trifluoride diethyl etherate (0.332mol, 1.2eq), and keeping the temperature at-30 to-20 ℃ after dropwise adding until the reaction is completely monitored by TLC (the petroleum ether, ethyl acetate and 6: 1 are used as developing agents, and the reaction is completely carried out when the compound N-10-a does not exist); controlling the temperature to be below minus 20 ℃, dropwise adding 600ml of saturated sodium bicarbonate solution, stirring for 0.5h, standing, separating liquid, taking an organic phase, washing with 600ml of saturated saline, drying by anhydrous sodium sulfate, concentrating under reduced pressure until no fraction is obtained, adding N-heptane, stirring, crystallizing, filtering, and drying to obtain the compound N-11125 g.
S3. product TY702
Figure BDA0002695098320000072
Preparation of
Mixing 140g of compound N-11(0.2mol, 1.0eq), 120g of pentamethylbenzene (0.8mol, 4.0eq) and 2800ml of dichloromethane, stirring until the mixture is dissolved, cooling, controlling the temperature to be minus 50 ℃ to minus 45 ℃, adding 1000ml of 1M dichloromethane solution of boron trichloride (1.0mol, 5.0eq), stirring for 1h under the condition of heat preservation after dripping is finished until TLC monitors that the reaction is complete (the reaction is complete when petroleum ether and ethyl acetate are used as developing agents and no compound N-11 exists); controlling the temperature to be below minus 20 ℃, dropwise adding 60g of triethylamine (0.6mol, 3.0eq) to terminate the reaction, washing with 1500ml of saturated sodium bicarbonate solution, washing with 1500ml of purified water, drying with anhydrous sodium sulfate, concentrating under reduced pressure until no fraction is formed, adding 2100ml of n-heptane, stirring, crystallizing, filtering and drying to obtain the product TY 70275 g.
S4, recrystallizing
And (2) mixing 75g of the product TY702 obtained in the step S3 with 1500ml of a mixed solvent (composed of ethyl acetate and n-heptane according to a mass ratio of 2: 1), heating to 60 ℃, dissolving and clarifying, carrying out heat filtration, slowly cooling to 25 ℃, controlling the cooling time to be 4h, filtering, and drying to obtain 63g of tylosin.
Example 2-3 preparation method of tylosin
The difference from example 1 is that the raw material charging amounts of examples 2 to 3 are different, specifically, see table 1.
TABLE 1
Figure BDA0002695098320000071
Figure BDA0002695098320000081
The preparation method is similar to example 1.
Comparative example 1 preparation method of tylosin
Similar to example 1, except that recrystallization was not performed.
Comparative example 2, method for preparing tylosin
Similar to example 1, except that pentamethylbenzene was not added in step S3.
Comparative example 3 preparation method of tylosin
The preparation method is carried out according to the following synthetic route:
Figure BDA0002695098320000082
mixing the obtained intermediate 3 with 1500ml of mixed solvent (composed of ethyl acetate and n-heptane according to the mass ratio of 2: 1), heating to 60 ℃, dissolving and clarifying, carrying out hot filtration, slowly cooling to 25 ℃, controlling the cooling time to be 4h, filtering, and drying to obtain the tylosin 1.
Comparative example 4 preparation method of tylosin
Intermediate 3 of comparative example 3 was acetylated and deacetylated, the specific synthetic route being:
Figure BDA0002695098320000091
mixing the obtained intermediate 5 with 1500ml of mixed solvent (composed of ethyl acetate and n-heptane according to the mass ratio of 2: 1), heating to 60 ℃, dissolving and clarifying, performing heat filtration, slowly cooling to 25 ℃, controlling the cooling time to be 4h, filtering, and drying to obtain the tylosin 2.
Experiment one, calculation of yield
TABLE 2
Figure BDA0002695098320000092
As can be seen from table 2, the yield of the TY702 product obtained in examples 1 to 3, i.e., tagagliflozin, is high, and the yield of the purified tagagliflozin obtained after recrystallization is also high. Comparative example 2, compared to example 1, without the addition of pentamethylbenzene, gave a lower yield of the product TY702 and purified tagagliflozin after recrystallization, and the yields of comparative example 3 and comparative example 4 were also lower than example 2.
Quality detection of test II, Ticageven
TABLE 3
Figure BDA0002695098320000101
The known impurity TY702-Bn has the structure
Figure BDA0002695098320000102
The source is due to the effect of the gram-binding reaction of compound N-11 upon debenzylation. As can be seen from Table 1, examples 1 to 3 have a lower content of the known impurity TY702-Bn, the largest individual impurities and total impurities, while comparative example 2 has a higher content of the known impurity TY702-Bn than example 1 without the addition of pentamethylbenzene, indicating that the addition of pentamethylbenzene in step S3 of the synthetic route is effective in suppressing the generation of the known impurity TY702-Bn and that recrystallization does not remove the known impurity TY 702-Bn; comparative example 3 the known impurity TY702-Bn is higher; the lower content of the known impurity TY702-Bn of comparative example 4 indicates that the known impurity TY702-Bn can be removed after acetylation and deacetylation procedures have been used, but the content is still higher than in example 1.
Test III, stability test of tylagliflozin
The test method comprises the following steps: accelerated stability test is carried out on the Ticagrelnet by referring to Chinese pharmacopoeia (2015 edition fourth general rule 9001 guiding principle of raw material drug and preparation stability test), and water, related substances and contents are respectively sampled and measured at the end of 0, 1,2, 3 and 6 months during the test period.
TABLE 4
Figure BDA0002695098320000111
As can be seen from table 4, examples 1 to 3 exhibited good stability with little change in moisture, total impurity content, and content in the accelerated stability test.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims (7)

1. The preparation method of the tylosin is characterized by comprising the following steps of:
s1) taking the compound N-9 and anhydrous tetrahydrofuran, stirring, replacing with nitrogen for three times, cooling, controlling the temperature to be minus 80 to minus 75 ℃, dropwise adding N-hexane solution of N-butyllithium for 1 to 2 hours, and stirring for 1 hour after dropwise adding; continuously controlling the temperature to be minus 80 to minus 75 ℃, dropwise adding a tetrahydrofuran solution of a compound N-8 for 1 to 2 hours, and keeping the temperature and stirring for 1.5 to 3 hours after the dropwise adding is finished until the TLC monitors the reaction to be complete; controlling the temperature to be below-20 ℃, dropwise adding an ammonium chloride aqueous solution, then returning the temperature to 10-15 ℃, extracting with dichloromethane, taking an organic phase, washing with saturated saline, drying, and concentrating under reduced pressure until no fraction is obtained to obtain a compound N-10-a;
s2) diluting and dissolving the compound N-10-a in the step S1 by using dichloromethane, adding triethylsilane, cooling to-30 ℃ under the protection of nitrogen, dropwise adding boron trifluoride diethyl etherate, and keeping the temperature at-20 to-30 ℃ after dropwise adding until the TLC monitoring reaction is completed; controlling the temperature to be below-20 ℃, dropwise adding a saturated sodium bicarbonate solution, stirring for 0.5-1 h, standing, separating liquid, taking an organic phase, washing with saturated brine, drying, concentrating under reduced pressure until no fraction is produced, adding N-heptane, stirring, crystallizing, filtering, and drying to obtain a compound N-11;
s3) mixing and stirring the compound N-11, the compound A and dichloromethane in the step S2 until the mixture is dissolved, cooling, controlling the temperature to be minus 50 ℃ to minus 45 ℃, adding a dichloromethane solution of Lewis acid, and keeping the temperature and stirring for 0.5-1 h after the dropping is finished until the TLC monitoring reaction is complete; controlling the temperature to be below-20 ℃, dropwise adding triethylamine to stop the reaction, washing with a saturated sodium bicarbonate solution, washing with purified water, drying, concentrating under reduced pressure until no fraction is produced, adding n-heptane, stirring for crystallization, filtering, and drying to obtain a product;
Figure 880407DEST_PATH_IMAGE001
compound N-9;
Figure 711834DEST_PATH_IMAGE002
compound N-8;
Figure 526206DEST_PATH_IMAGE003
N-10-a；
Figure 348669DEST_PATH_IMAGE004
compound N-11;
the Lewis acid is boron trichloride;
the compound A is trimethylbenzene or pentamethylbenzene.
2. The process for producing tylosin according to claim 1, wherein the equivalent ratio of the compound N-9, N-butyllithium and the compound N-8 in the step S1 is (1 to 1.5): (1-1.5): 1.
3. the method for preparing tylosin according to claim 1, wherein the equivalent ratio of the compound N-9, triethylsilane and boron trifluoride etherate is (1 to 1.5): (1.5-2): (1-1.5).
4. The method for preparing tylosin according to claim 1, wherein the equivalent ratio of the compound N-11 to the lewis acid in the step S3 is 1: (5-10).
5. The process for producing tylosin according to claim 1, wherein the equivalent ratio of compound N-11 to compound a in step S3 is 1: (3-8).
6. The preparation method of tylosin according to claim 1, further comprising recrystallization, wherein the recrystallization comprises the following specific steps: and (5) mixing the product obtained in the step (S3) with the mixed solvent, heating to 60 ℃, dissolving and clarifying, carrying out hot filtration, slowly cooling to 25-30 ℃, controlling the cooling time to be 4-6 h, filtering, and drying to obtain the product.
7. The method for preparing tylosin according to claim 6, wherein the mixed solvent is prepared from ethyl acetate and n-heptane in a ratio of 2: 1, in terms of mass ratio.
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