CN116253741A - Synthesis method of belotekang derivative - Google Patents

Synthesis method of belotekang derivative Download PDF

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CN116253741A
CN116253741A CN202211724254.9A CN202211724254A CN116253741A CN 116253741 A CN116253741 A CN 116253741A CN 202211724254 A CN202211724254 A CN 202211724254A CN 116253741 A CN116253741 A CN 116253741A
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吕伟
金嵇煜
金沉
朱瑞
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Shanghai Xiyao Pharmaceutical Technology Co ltd
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract

The invention provides a synthesis method of a belotecan derivative, which comprises the following steps: dissolving the compound IV in an acid solution, stirring, adding an inorganic alkali solution to adjust the pH to 8 after the reaction is completed, extracting by an organic solvent, mixing and drying organic phases, and separating and purifying by using a silica gel column chromatography to obtain the compound V; adding the compound V, the compound VI, the pyridine p-toluenesulfonate and the o-cresol into toluene under nitrogen flow, stirring, filtering and drying after the reaction is completed to obtain a compound VII; and (3) dissolving the compound VII in an acidic solution, stirring, adding an ether reagent after the reaction is completed to obtain a solid, and filtering to obtain a product VIII. Compared with the prior art, the synthesis method has high yield and low cost, and is suitable for industrial production.

Description

Synthesis method of belotekang derivative
Technical Field
The invention relates to the field of medicine synthesis, in particular to a synthesis method of an anti-tumor medicine belatine derivative, in particular to a hydrochloride thereof.
Background
Belotekang hydrochloride is a camptothecin derivative, has topoisomerase I (TOP I) inhibitory activity, is developed by Chong Kun Dang pharmacy, is approved by KFDA in Korea on 12 th year 10, and is marketed by Chong Kun Dang in Korea under the trade name of
Figure SMS_1
Can be used for treating non-small cell lung cancer and ovarian cancer.
The synthesis of belotecan mainly comprises two methods: the total synthesis method and the semisynthesis method are specifically described below.
Total synthesis method
In 1996, sang-sup Jew et al in Korea used o-nitroacetophenone as a raw material, and obtained belotekang through five reactions of Mannich reaction, benzoyl protection, sodium hydrosulfite reduction, ring formation reaction and deprotection. In the total synthesis method, the total yield of the belotecan is about 1.86%, the yield is too low, the actual production cost is particularly high, and the significance is low.
Figure SMS_2
Semi-synthetic method
In 2000, soon Kil Ahn et al in Korea prepared belotekang by methylation and Mannich reaction of camptothecin as a raw material, and the reaction formula is shown below. In the semisynthesis method, the final step has a large amount of Mannich reaction byproducts, low yield and difficult purification, and influences the application of the route.
Figure SMS_3
Thus, there remains a need for a process for the preparation of belatinecan derivatives, in particular the hydrochloride salts thereof, which is simple in process, high in yield and low in cost.
Disclosure of Invention
The invention aims to provide a synthesis method of an antitumor drug belotecan derivative, namely, a target compound belotecan hydrochloride is finally obtained by taking cheap and easily available tryptamine as a starting material and carrying out reductive amination, upper protecting group, oxidative cleavage of double bonds, deformyl removal, friedlander condensation and deprotection. The invention has the advantages that: compared with the prior art, the method has high yield and low cost, and is suitable for industrial production.
According to one embodiment of the present invention, there is provided:
a method for the total synthesis of a belotecan derivative, the method comprising the steps of:
step 4: dissolving the compound IV in an acidic solution, stirring, adding an inorganic alkali solution to adjust the pH to 8 after the reaction is completed, extracting with an organic solvent for preferably three times, merging and drying the organic phases, and separating and purifying by using a silica gel column chromatography to obtain the compound V;
Figure SMS_4
preferably, in step 4, the process comprises,
the acidic solution is selected from hydrochloric acid/methanol solution, acetic acid, trifluoroacetic acid, preferably hydrochloric acid/methanol solution;
the inorganic alkali solution is saturated sodium bicarbonate solution or saturated sodium carbonate solution,
the organic solvent is dichloromethane or ethyl acetate,
wherein G is selected from
Figure SMS_5
Preferably +.>
Figure SMS_6
The reaction temperature is 10 to 100 ℃, preferably 65 ℃,
the reaction time is 0.5 to 10 hours, preferably 1 hour;
step 5: adding the compound V, the compound VI, the pyridine p-toluenesulfonate and the o-cresol into toluene under nitrogen flow, stirring, filtering and drying after the reaction is completed to obtain a compound VII;
Figure SMS_7
/>
wherein G is selected from
Figure SMS_8
Preferably +.>
Figure SMS_9
Preferably, the reaction temperature is 80 to 150 ℃, preferably 110 ℃;
the reaction time is 10 to 40 hours, preferably 24 hours;
step 6: and (3) dissolving the compound VII in an acidic solution, stirring, adding an ether reagent after the reaction is completed to obtain a solid, and filtering to obtain a product VIII.
Figure SMS_10
Wherein G is selected from
Figure SMS_11
Preferably->
Figure SMS_12
Wherein, the acid solution is: hydrogen chloride/methanol solution, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, preferably hydrogen chloride/methanol solution; namely, HX is hydrogen chloride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, preferably hydrogen chloride, respectively;
preferably, the ether agent is selected from dimethyl ether, diethyl ether, methyl ethyl ether, methyl tertiary butyl ether, petroleum ether, preferably methyl tertiary butyl ether;
the reaction temperature is 10-100 ℃, preferably 65 ℃;
the reaction time is 1 to 24 hours, preferably 16 hours.
According to one embodiment of the invention, the method further comprises:
step 3: adding the compound III and alcohol into a reaction bottle, slowly adding an oxidant under ice bath, stirring, evaporating the alcohol under reduced pressure after the reaction is completed, extracting the alcohol preferably three times by using an organic solvent, merging and drying organic phases, concentrating to obtain a crude product, and separating and purifying by using a silica gel column chromatography to obtain a compound IV;
Figure SMS_13
/>
wherein G is selected from
Figure SMS_14
Preferably +.>
Figure SMS_15
Wherein, preferably, the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, preferably the alcohol is methanol or ethanol;
the oxidant is selected from sodium periodate, sodium hypochlorite, hydrogen peroxide and potassium permanganate, and sodium periodate is preferred;
the organic solvent is dichloromethane or ethyl acetate;
the molar ratio of the compound III to the oxidant is 1:1 to 1:10, preferably 1:3, a step of;
the reaction temperature is 10-40 ℃, preferably 25 ℃;
the reaction time is 1 to 24 hours, preferably 16 hours.
According to one embodiment of the invention, the method further comprises:
step 2: adding the compound II, organic base, a protective reagent and an aprotic solvent into a reaction bottle, stirring, and separating and purifying by using silica gel column chromatography after the reaction is completed to obtain a compound III;
Figure SMS_16
wherein G is selected from
Figure SMS_17
Preferably +.>
Figure SMS_18
Wherein, preferably
The organic base is triethylamine or N, N-diisopropylethylamine;
the protecting agent is selected from acetic anhydride, trifluoroacetic anhydride, benzyl chloroformate, di-tert-butyl dicarbonate, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, preferably acetic anhydride;
the aprotic solvent is dichloromethane or ethyl acetate;
the molar ratio of compound II to the protecting agent is 1:1 to 1:3, preferably 1:1.5;
the reaction temperature is 10-40 ℃, preferably 25 ℃;
the reaction time is 1 to 24 hours, preferably 16 hours;
according to one embodiment of the invention, the method further comprises:
step 1: under the nitrogen flow, tryptamine (compound I), reducing agent, acetic acid and methanol are added into a reaction flask, a mixed solution of acetone and methanol is slowly added dropwise, after the reaction is completed, 2M sodium carbonate solution is added to adjust the pH to 8-9, methanol is distilled off under reduced pressure, extraction of methylene dichloride is preferably performed for three times, and organic phases are combined and dried, and then the compound II is obtained after concentration.
Figure SMS_19
Wherein preferably the reducing agent is selected from sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, preferably sodium cyanoborohydride;
the mole ratio of tryptamine (compound I), acetone, reducing agent and acetic acid is 1: (1-2): (1-2): (1-4), preferably 1:1:2:4, a step of;
the reaction temperature is 10-40 ℃, preferably 25 ℃;
the reaction time is 1 to 24 hours, preferably 16 hours.
Advantageous effects
The synthesis method of the invention takes cheap and easily available tryptamine as a starting material, and finally obtains the target compound belotecan derivative through reductive amination, upper protecting group, oxidative cleavage of double bond, deformyl removal, friedlander condensation and deprotection. Compared with the prior art, the invention has high yield and low cost, and is suitable for industrial production.
Drawings
Fig. 1 shows a schematic route of a reaction formula of a production method according to an embodiment of the present invention.
Fig. 2 shows a schematic route of a reaction formula of a production method according to another embodiment of the present invention.
Fig. 3 shows a schematic route of a reaction formula of a production method according to another embodiment of the present invention.
Fig. 4 shows a schematic route of a reaction formula of a production method according to another embodiment of the present invention.
Detailed Description
In the following examples, the synthesis of the antineoplastic drug beloxsulam hydrochloride according to the present invention will be described in detail, but the examples do not constitute a limitation of the present invention.
In the following examples, the starting materials used were all purchased from Shanghai Taitan technologies, inc., unless otherwise specified.
Example 1.
Figure SMS_20
Under a nitrogen stream, tryptamine (8 g,1.0 eq), sodium cyanoborohydride (6.28 g,2.0 eq), acetic acid (11.42 mL,4 eq), methanol (80 mL) were added to the reaction flask, and a mixed solution of acetone (3.67 mL,1.0 eq) and methanol (80 mL) was slowly added dropwise and stirred at room temperature for 16 hours. TLC monitoring reaction completion, adding 2M sodium carbonate solution to adjust pH to 8-9, decompressing and distilling off methanol, adding water, extracting three times with dichloromethane, merging and drying organic phases, concentrating to obtain 9.4g of compound II with the yield of 94%.
1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.04(s,2H),7.60(d,J＝7.8Hz,1H),7.37(d,J＝8.1Hz,1H),7.26(d,J＝2.1Hz,1H),7.09(t,J＝7.5Hz,1H),7.01(t,J＝7.4Hz,1H),3.35-3.25(m,1H),3.11(s,4H),1.27(d,J＝6.5Hz,6H).
Example 2
Figure SMS_21
Compound II (9.4 g,1 eq), triethylamine (4.7 mL,2.0 eq), acetic anhydride (6.5 mL,1.5 eq), dichloromethane (94 mL) were added to the reaction flask and stirred at room temperature for 16h. TLC monitoring the reaction completion, separating and purifying by silica gel column chromatography to obtain compound III 10.2g, yield 90%.
1 H NMR(400MHz,DMSO-d6)δ10.85(d,J＝38.7Hz,1H),7.59(dd,J＝37.4,7.8Hz,1H),7.34(t,J＝8.7Hz,1H),7.20(dd,J＝35.5,2.2Hz,1H),7.03(dq,J＝31.8,7.6Hz,2H),4.28(ddq,J＝181.3,13.3,6.8Hz,1H),3.41-3.36(m,1H),3.00-2.76(m,2H),2.05(d,J＝17.6Hz,3H),1.16(dd,J＝6.9,2.5Hz,6H).
Example 3
Figure SMS_22
Compound III (10.2 g,1 eq), 612mL of methanol, was added to the reaction flask, and 714mL of an aqueous solution of sodium periodate (21 g,3 eq) was slowly dropped under ice bath, and stirred at room temperature for 16h. TLC monitoring reaction completely, vacuum evaporating methanol, extracting aqueous solution with dichloromethane three times, combining and drying organic phases, concentrating to obtain crude product, separating and purifying by silica gel column chromatography to obtain compound IV 9.6g, yield 83%.
Example 4
Figure SMS_23
4.8mL of concentrated hydrochloric acid and 48mL of methanol are taken to prepare a mixed solution, compound V (9.6 g,1 eq) is dissolved in the mixed solution of hydrochloric acid and methanol, the mixed solution is stirred for 1 hour at 65 ℃, TLC monitoring reaction is completed, saturated sodium carbonate solution is added to adjust pH to 8, dichloromethane is used for extraction three times, organic phases are combined and dried, and silica gel column chromatography is used for separation and purification, so that 7.3g of compound V is obtained, and the yield is 85%.
1 H NMR(400MHz,DMSO-d6)δ7.80-7.26(m,1H),7.25-7.20(m,3H),6.77-6.74(m,1H),6.56-6.51(m,1H),4.49-4.00(m,1H),3.54-3.39(m，2H),3.25-3.08(m,2H),2.04-2.01(m,3H),1.15-1.08(m,6H).
Example 5
Figure SMS_24
Compound V (7.3 g,1.0 eq), compound VI (9.3 g,1.2 eq), pyridine p-toluenesulfonate (2.2 g,0.3 eq), o-cresol (22.2 g,7.0 eq) and toluene (146 mL) were added to a reaction flask under nitrogen flow, heated to reflux (internal temperature 110 ℃, water was removed by separation), reacted for 24 hours, detected by HPLC, cooled to room temperature, stirred for 2 hours, filtered, dried to give compound VII as a yellow solid 10.9g, yield 78%.
Example 6
Figure SMS_25
10.9g of compound VII is dissolved in 109mL of saturated hydrogen chloride methanol solution, stirred for 16 hours at 65 ℃, TLC is monitored to complete the reaction, most of methanol is removed by screwing, 109mL of methyl tertiary butyl ether is added to form a large amount of solid, filtering and drying are carried out, and 9.0g of yellow solid product belatine hydrochloride (compound VIII) is obtained, and the yield is 83%.
1 H NMR(400MHz,DMSO-d6)δ9.30(broad s,2H)，8.42(d,1H,J＝8.4Hz)，8.17(d,1H,J＝8.4Hz),7.86(dd,1H,J＝8.4,8.0Hz),7.74(dd,1H,J＝8.4,8.0Hz),7.32(s,1H),5.37(s,2H),5.43(s,2H)，3.60-3.64(m,2H),3.34-3.45(m,1H),3.13-3.19(m,2H),1.83-1.90(m,2H),1.26(d,6H,J＝6.4Hz),0.87(t,3H,J＝8.0Hz).
From the above examples, it can be seen that the process according to the examples of the present invention produces belote hydrochloride in an overall yield of 38.6% from inexpensive raw materials, and is mild in reaction conditions, safe in reaction reagents, and easy in the disposal of reaction by-products and waste liquids, and is particularly suitable for industrial use.

Claims (9)

1. A method for synthesizing a belotecan derivative, the method comprising the steps of:
step 4: dissolving the compound IV in an acid solution, stirring, adding an inorganic alkali solution to adjust the pH to 8 after the reaction is completed, extracting by an organic solvent, mixing and drying organic phases, and separating and purifying by using a silica gel column chromatography to obtain the compound V;
Figure FDA0004029037520000011
step 5: adding the compound V, the compound VI, the pyridine p-toluenesulfonate and the o-cresol into toluene under nitrogen flow, stirring, filtering and drying after the reaction is completed to obtain a compound VII;
Figure FDA0004029037520000012
step 6: dissolving a compound VII in an acidic solution, stirring, adding an ether reagent after complete reaction to obtain a solid, filtering to obtain a product VIII,
Figure FDA0004029037520000013
in step 6, the acidic solution is: hydrogen chloride/methanol solution, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid; namely, HX is hydrogen chloride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, respectively;
wherein G is selected from
Figure FDA0004029037520000021
2. The method of claim 1, wherein,
in step 4, the acidic solution is selected from the group consisting of hydrochloric acid/methanol solution, acetic acid, trifluoroacetic acid;
the inorganic alkali solution is saturated sodium bicarbonate solution or saturated sodium carbonate solution,
the organic solvent is dichloromethane or ethyl acetate,
the reaction temperature is 10-100 ℃;
the reaction time is 0.5-10 hours;
and/or
In the step 5 of the process, the process is carried out,
the reaction temperature is 80-150 ℃;
the reaction time is 10 to 40 hours;
and/or
In the step (6) of the process,
the ether reagent is selected from dimethyl ether, diethyl ether, methyl ethyl ether, methyl tertiary butyl ether and petroleum ether;
the reaction temperature is 10-100 ℃;
the reaction time is 1-24 hours.
3. The method of claim 1, wherein G is
Figure FDA0004029037520000022
In the step 4, the acid solution is hydrochloric acid/methanol solution, the reaction temperature is 65 ℃, and the reaction time is 1 hour;
in step 5, the reaction temperature is 110 ℃ and the reaction time is 24 hours;
in step 6, the acidic solution is a hydrogen chloride/methanol solution, corresponding HX is hydrogen chloride, the reaction temperature is 65 ℃, the reaction time is 16 hours, and the ether reagent is methyl tertiary butyl ether.
4. A method according to any one of claims 1 to 3, the method further comprising:
step 3: adding the compound III and alcohol into a reaction bottle, slowly adding an oxidant under ice bath, stirring, evaporating the alcohol under reduced pressure after the reaction is completed, extracting with an organic solvent, merging and drying organic phases, concentrating to obtain a crude product, and separating and purifying by using a silica gel column chromatography to obtain a compound IV;
Figure FDA0004029037520000031
wherein G is as defined in any one of claims 1 to 3,
preferably, in step 3, the process comprises,
the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol,
the oxidant is selected from sodium periodate, sodium hypochlorite, hydrogen peroxide and potassium permanganate;
the organic solvent is dichloromethane or ethyl acetate;
the molar ratio of the compound III to the oxidant is 1:1 to 1:10;
the reaction temperature is 10-40 ℃;
the reaction time is 1-24 hours.
5. The method of claim 4, wherein G is
Figure FDA0004029037520000032
In the step 3, the alcohol is methanol or ethanol, the oxidant is sodium periodate, and the molar ratio of the compound III to the oxidant is 1:3, the reaction temperature is 25 ℃; the reaction time was 16 hours.
6. The method of claim 4, the method further comprising:
step 2: adding the compound II, organic base, a protective reagent and an aprotic solvent into a reaction bottle, stirring, and separating and purifying by using silica gel column chromatography after the reaction is completed to obtain a compound III;
Figure FDA0004029037520000033
preferably, in step 2, the organic base is triethylamine or N, N-diisopropylethylamine; the protecting agent is selected from acetic anhydride, trifluoroacetic anhydride, benzyl chloroformate, di-tert-butyl dicarbonate, methanesulfonyl chloride and trifluoromethanesulfonic anhydride; the aprotic solvent is dichloromethane or ethyl acetate;
the molar ratio of compound II to the protecting agent is 1:1 to 1:3, a step of;
the reaction temperature is 10-40 ℃;
the reaction time is 1-24 hours.
7. The method of claim 6, wherein G is
Figure FDA0004029037520000034
In step 2, the protecting agent is acetic anhydride; the molar ratio of compound II to the protecting agent is 1:1.5; the reaction temperature is 25 ℃; the reaction time was 16 hours.
8. The method of claim 6, the method further comprising:
step 1: adding the compound I, a reducing agent, acetic acid and methanol into a reaction flask under nitrogen flow, slowly dropwise adding a mixed solution of acetone and methanol, after the reaction is completed, adding a 2M sodium carbonate solution to adjust the pH to 8-9, evaporating the methanol under reduced pressure, extracting with dichloromethane, merging and drying organic phases, concentrating to obtain a compound II,
Figure FDA0004029037520000041
preferably, in step 1, the reducing agent is selected from sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride;
the molar ratio of the compound I to the acetone to the reducing agent to the acetic acid is 1: (1-2): (1-2): (1-4);
the reaction temperature is 10-40 ℃;
the reaction time is 1-24 hours.
9. The method according to claim 8, wherein the method comprises,
in step 1, the reducing agent is sodium cyanoborohydride; the molar ratio of the compound I to the acetone to the reducing agent to the acetic acid is 1:1:2:4, a step of; the reaction temperature is 25 ℃; the reaction time was 16 hours.
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