CN114315755B - Synthesis method of key intermediate of Tubulysin and analogues thereof - Google Patents
Synthesis method of key intermediate of Tubulysin and analogues thereof Download PDFInfo
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Abstract
A method for synthesizing key intermediates of Tubulysin and analogues thereof. The invention provides a method for synthesizing a compound A, which comprises the following steps:
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for synthesizing a key intermediate of a cytotoxin molecule Tubulysin and an analogue thereof, which are suitable for targeted therapy.
Background
The TUV fragment (compound A) is a key intermediate of a compound of the family of synthetic natural anticancer drugs, the structural formula is shown below, and the TUV fragment (compound A) and the Tubumysin and analogues thereof have the following structures:
tubulysins not only has very high anticancer activity, but also can effectively inhibit the growth of drug-resistant cancer cells, but its specific mechanism of action is contrary to epothilones and paclitaxel, i.e. promotes the polymerization of tubulin. In addition, tubulysins was found to have an angiogenesis inhibiting effect. These all illustrate the great potential of Tubulysins as anticancer agents, which are not only ideal candidates for incorporation into Small Molecule Drug Conjugate (SMDC) delivery systems, but also as ADC payloads, have been fully focused and studied.
CN110684044a discloses a method for preparing a key fragment Tuv of Tubulysin, the reaction formula is as follows:
p represents a protecting group for a nitrogen atom, in particular Boc, cbz, COOMe or COOEt, P 1 Represents an oxygen atom protecting group, in particular TBS, TES, TBDPS, bn, PMB, ac, R, R 1 And R is 2 Represents different aryl or alkyl substituents.
CN104072578B discloses a method for preparing natural product Tubulysin U, wherein the preparation method of Tuv fragment is as follows:
CN110684044a and CN104072578B disclose a preparation method of Tuv, which has many route steps, uses multiple dangerous reagents, has no cost advantage, and is not suitable for industrial production.
WO2017134547A1 discloses the following routes, compound a as a key intermediate:
the route has obvious advantages, and avoids the use of dangerous reagents such as azide, sodium hydrogen, periodic acid and the like; compound a is a key intermediate for this route, and overall yield is also higher, but there is no cost advantage. Similar methods are reported in WO2017134547A1, WO2017054080 and j.org.chem.2008,73, 4362-4369:
the current literature reports that compound 1 is cyclized with paraformaldehyde to generate intermediate 2, then reduced with sodium cyanoborohydride to generate compound 3 through deprotection; according to the route of the analogue reported in the literature, the raw material purification difficulty is high, and the intermediate is unstable; the first step of cyclization reaction is slow, takes a long time and requires a closed pot reaction; sodium cyanoborohydride and hydrochloric acid are used for reduction, and the risk of releasing highly toxic hydrogen cyanide exists; this scheme has a limited range of use and can only produce N-methyl compounds.
In view of the above, the synthesis of compound a has significant drawbacks, and therefore, finding a better synthesis route is of great importance, and more suitable synthesis methods need to be developed.
The invention comprises the following steps:
based on the technical problems in the background technology, the process route of the compound A has urgent needs and broad prospects. The invention provides a synthesis method of a key intermediate (compound A) of Tubulysin and analogues thereof, which has the advantages of mild reaction conditions, environment friendliness, novel route, simple post-treatment and purification, and the prepared compound A has the advantages of good purity, high yield, low cost and easy mass production.
The invention provides a synthesis process of a compound A, which comprises the following synthesis routes:
r is selected from C1-C6 fatty alkyl, preferably methyl, ethyl, propyl, isopropyl or butyl, most preferably methyl;
r' is selected from methyl or ethyl;
ar is selected from phenyl or substituted phenyl, and the substituted phenyl is selected from p-methoxyphenyl, p-nitrobenzyl, 2, 4-dimethoxybenzyl and the like;
the method comprises the following steps:
s1: taking a compound B as a raw material, and carrying out reductive amination reaction with ArCHO to obtain a compound C;
s2: then carrying out reductive amination reaction with RCHO to obtain a compound D;
s3: and carrying out deprotection reaction on the compound D to obtain a compound A.
The invention further provides the following scheme: the reaction solvent of step S1 is selected from DCM, THF, acetonitrile, toluene or methanol, preferably DCM or THF;
the invention further provides the following scheme: arCHO of step S1 is selected from benzaldehyde, p-methoxybenzaldehyde, p-nitrobenzaldehyde, 2, 4-dimethoxybenzaldehyde, etc., preferably benzaldehyde;
the invention further provides the following scheme: the reductive amination of step S1 uses a reducing agent selected from NaBH (OAc) 3 ，NaBH 4 ，NaBH 3 CN，Et 3 SiH, etc., preferably NaBH (OAc) 3 ；
The invention further provides the following scheme: in the step S1, the compound B uses hydrochloride, and after optional alkali (such as triethylamine) is dissociated, the compound B and ArCHO are subjected to reductive amination reaction or simultaneously added with alkali (such as triethylamine) and a reducing agent for one-pot reaction;
the invention further provides the following scheme: step S1 is carried out at a reaction temperature of 0 to 50℃and preferably 20 to 30 ℃.
The invention further provides the following scheme: step S2 the reaction solvent is selected from DCM, THF, acetonitrile, toluene or methanol, preferably DCM or THF;
the invention further provides the following scheme: RCHO in step S2 is selected from formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, etc.;
the invention further provides the following scheme: the reductive amination of step S2 uses a reducing agent selected from NaBH (OAc) 3 ，NaBH 4 ，NaBH 3 CN，Et 3 SiH, etc., preferably NaBH (OAc) 3 ；
The invention further provides the following scheme: step S2 is carried out at a reaction temperature of 0 to 50℃and preferably 20 to 30 ℃.
The invention further provides the following scheme: in step S3 deprotection reaction, when Ar is selected from phenyl, S3 deprotection reaction is selected from hydrogenation deprotection scheme: when Ar is selected from substituted phenyl, the substituted phenyl is selected from p-methoxyphenyl, p-nitrobenzyl and 2, 4-dimethoxybenzyl, the S3 deprotection reaction is selected from oxidation deprotection reaction or acid deprotection reaction;
the preferred technical scheme of the invention is as follows:
when Ar is selected from phenyl, the S3 deprotection reaction is selected from the process-hydrogenation deprotection scheme:
method one, hydrodeprotection scheme:
the invention further provides the following scheme: the hydrogenation deprotection in step S3 is carried out in a solvent such as methanol, ethanol, THF, acetonitrile, etc., preferably methanol;
the invention further provides the following scheme: in the step S3, the deprotection of the hydrogenation reaction is carried out under the action of a catalyst and a hydrogen source;
the invention further provides the following scheme: the hydrogenation deprotection catalyst in the step S3 is selected from palladium carbon, platinum carbon, raney Ni and the like, preferably palladium carbon;
the invention further provides the following scheme: the hydrogen source deprotected by the hydrogenation in step S3 is selected from hydrogen, ammonium formate, formic acid or cyclohexadiene, preferably hydrogen;
the invention further provides the following scheme: the hydrogenation deprotection in step S3 is carried out at a reaction temperature of 0-50 ℃, preferably 20-30 ℃;
when Ar is selected from substituted phenyl, the S3 deprotection reaction is selected from a process oxidative deprotection scheme or a process three S3 acid deprotection scheme:
method two, S3 oxidation deprotection scheme:
the invention further provides the following scheme: oxidative deprotection in step S3 is performed in acetonitrile, ethanol, THF, water, etc., preferably acetonitrile;
the invention further provides the following scheme: in the step S3, oxidation deprotection is reacted under the action of an oxidant;
the invention further provides the following scheme: the oxidant for oxidative deprotection in the step S3 is selected from potassium persulfate, DDQ, hydrogen peroxide and the like, preferably potassium persulfate;
the invention further provides the following scheme: the oxidation deprotection in the step S3 is carried out at a reaction temperature of 20-100 ℃, preferably 65-70 ℃;
method three, S3 acid deprotection scheme:
the invention further provides the following scheme: the acid deprotected in step S3 is selected from trifluoroacetic acid, sulfuric acid, methanesulfonic acid, etc., preferably trifluoroacetic acid;
the invention further provides the following scheme: the acid deprotection in step S3 is carried out at a reaction temperature of 60-120 ℃, preferably 70-80 ℃;
the invention further provides the following scheme: in the step S3, the reaction is carried out under a solvent-free system;
the invention further provides the following scheme: the acid volume amount of the acid deprotecting acid in step S3 is 1 to 20 times, preferably 10 to 15 times the volume amount of the compound D (starting material).
The present invention also provides a novel intermediate compound:
r' is selected from methyl or ethyl;
R 1 selected from phenyl or substituted phenyl, substituted phenyl selected from p-methoxyphenyl, p-nitrophenyl, 2, 4-dimethoxybenzyl, preferably phenyl; r is R 2 Selected from p-methoxyphenyl, p-nitrophenyl or 2, 4-dimethoxybenzyl.
In a further aspect of the invention, there is provided a novel intermediate compound:
the invention also provides a method for preparing Tubulysin and analogues thereof, comprising the synthetic method or the intermediate compound.
The beneficial technical effects of the invention are as follows:
the invention directly adopts the compound B which is easy to purify as the starting material, and the compound B is hydrochloride and in solid form, thus being easy to operate; the compound B is subjected to reductive amination reaction to prepare a secondary amine intermediate, and then another reductive amination reaction is carried out to obtain a new tertiary amine intermediate, and the tertiary amine intermediate is subjected to hydrogenation deprotection or oxidation deprotection or acid deprotection selectively to obtain a new product. The whole reaction process does not use hazardous reagents such as azide and the like, does not use severe conditions, has good purification effect, is simple, convenient and quick, has mild and controllable reaction conditions, has the yield of more than 80% in each step, has high total yield and obvious cost advantage, and is easy for industrial production;
in particular, the prior art does not report on a preparation method for monosubstituted N methyl on a compound A, and the invention provides a method for monosubstituted monoalkylmethyl through ingenious design; the method utilizes benzyl or any substituted benzyl to protect amino, then the amino is subjected to reductive amination reaction with formaldehyde, and the benzyl or any substituted benzyl is removed to protect the intermediate of the monoalkyl methyl; the research blank in the field is realized, the reaction yield is high, the product quality is good, and the double alkylation impurities are avoided; the reaction has good selectivity, and simultaneously solves the problem of poor reaction selectivity in the prior art.
Detailed Description
The technical scheme of the invention is described in detail through specific embodiments. Including but not limited to the following examples.
Synthesis of Compound D:
r is selected from C1-C6 fatty alkyl, preferably methyl, ethyl, propyl, isopropyl or butyl, most preferably methyl;
r' is selected from methyl or ethyl;
ar is selected from phenyl or substituted phenyl, and the substituted phenyl is selected from p-methoxyphenyl, p-nitrobenzyl, 2, 4-dimethoxybenzyl and the like.
Example 1:
1.0g of Compound B was dissolved in 10mL of tetrahydrofuran, 0.4g of triethylamine and 0.5g of p-methoxybenzaldehyde were added thereto, and the mixture was stirred at room temperature for 1 hour; then adding 1.7g sodium borohydride acetate in batches, continuing stirring at room temperature for 3 hours, and monitoring the completion of the reaction by TLC;
dropwise adding saturated sodium bicarbonate aqueous solution into the reaction system until the pH is 7-8, standing for layering, and adding 10mL of ethyl acetate to extract a water phase; the organic phases were combined, washed once with 3mL of saturated saline, and the organic phase was concentrated to dryness to give Compound 1C (ESI m/z C) 20 H 28 N 2 O 4 S[M+H] + Calculated 393.2, measured 393.2) and directly carried on to the next step without purification;
10mL of THF (10 ml of THF) and 1mL of 37% formaldehyde aqueous solution are added into the crude product, the mixture is stirred for 3 hours at 20-30 ℃, TLC is free from raw materials, 1.7g of sodium borohydride acetate is added into the mixture, and the mixture is stirred for 18 hours for central control reaction;
adding saturated sodium bicarbonate aqueous solution into the reaction system until the pH value is 7-8, standing for layering, and adding ethyl acetate to extract a water phase; the organic phases were combined, washed once with 3mL of saturated brine, the organic phase concentrated to dryness and the crude product was chromatographed (DCM/meoh=20:1 elution) to give compound 1D:1.1g colorless oil, two-step yield: 83.5%;1H NMR (400 MHz, d 6-DMSO). Delta.8.42 (s, 1H), 7.25-7.23 (d, J=8.0 Hz, 2H), 6.87-6.85 (d, J=8.0 Hz, 2H), 6.63 (brs, 1H), 5.11-5.09 (m, 1H), 4.33-4.25 (m, 2H), 3.73 (s, 3H), 3.73-3.69 (dd, J=16.0 Hz, 1H), 3.58-3.55 (dd, J=12.0 Hz, 1H), 2.72-2.68 (m, 1H), 2.15 (s, 3H), 2.10-2.03 (m, 1H), 1.95-1.87 (m, 1H), 1.69-1.63 (m, 1H), 1.31-1.27 (t, J=8.0 Hz, 3H), 0.58-3.55 (dd, J=12.0 Hz, 1H), 2.72-2.68 (m, 1H), 2.69-1.63 (m, 1H), 0.69-1.9 (d=0 Hz, 0.0 Hz). ESI m/z C 21 H 30 N 2 O 4 S[M+H]Calculated 407.2, found 407.2.
Example 2:
3.0g of Compound B was dissolved in 30mL of tetrahydrofuran, 1.2g of triethylamine and 1.1g of benzaldehyde were added thereto, and the mixture was stirred at room temperature for 1 hour; then 5.1g sodium borohydride acetate was added in portions, stirring was continued at room temperature for 3 hours, and TLC was monitored for completion of the reaction;
dropwise adding saturated sodium bicarbonate aqueous solution into the reaction system until the pH is 7-8, standing for layering, and adding 30mL of ethyl acetate to extract a water phase; the organic phases were combined, washed once with 9mL of saturated saline, and the organic phase was concentrated to dryness to give Compound 2C (ESI m/z C) 19 H 26 N 2 O 3 S[M+H]Calculated 363.2, measured 363.1), directly proceeding to the next step without purification;
adding 30mL of THF and 3mL of 37% formaldehyde aqueous solution into the crude product, stirring for 3 hours at 20-30 ℃, adding 5.1g of sodium borohydride acetate into the crude product, stirring for 18 hours, and performing medium control reaction to complete, wherein TLC is free of raw materials; adding saturated sodium bicarbonate aqueous solution into the reaction system until the pH value is 7-8, standing for layering, and adding 30mL of ethyl acetate for extracting a water phase; the organic phases were combined, washed once with 9mL of saturated brine, the organic phase concentrated to dryness and the crude product was chromatographed (DCM/meoh=20:1 elution) to give compound 2D:2.9g colorless oil, two-step yield: 79.2%.1H NMR (400 MHz, d 6-DMSO). Delta.8.44 (s, 1H), 7.36-7.22 (m, 5H), 6.60 (brs, 1H), 5.14-5.12 (m, 1H), 4.33-4.27 (m, 2H), 3.81-3.78 (dd, J=12.0 Hz, 1H), 3.68-3.64 (dd, J=16.0 Hz, 1H), 2.76-2.71 (m, 1H), 2.18 (s, 3H), 2.12-2.05 (m, 1H), 1.97-1.92 (m, 1H), 1.71-1.64 (m, 1H), 1.32-1.29 (t, J=8.0 Hz, 3H), 0.97-0.96 (d, J=4.0 Hz, 3H), 0.92-0.90 (d, J=8.0 Hz, 3H). ESI m/z C 20 H 28 N 2 O 3 S[M+H] + Calculated 437.2, measured 437.2.
Example 3:
1.0g of Compound B was dissolved in 10mL of tetrahydrofuran, 0.4g of triethylamine and 0.57g of 2, 4-dimethoxybenzaldehyde were added thereto, and the mixture was stirred at room temperature for 1 hour; then adding 1.7g sodium borohydride acetate in batches, continuing stirring at room temperature for 3 hours, and monitoring the completion of the reaction by TLC;
reactionDropwise adding saturated sodium bicarbonate aqueous solution into the system until the pH is 7-8, standing for layering, and adding 10mL of ethyl acetate for extracting a water phase; the organic phases were combined, washed once with 3mL of saturated saline, and the organic phase was concentrated to dryness to give Compound 3C (ESI m/z C) 21 H 30 N 2 O 5 S[M+H] + Calculated 423.2, measured 423.1) and directly carried on to the next step without purification;
adding 10mL of THF and 1mL of 37% formaldehyde aqueous solution into the crude product, stirring for 3 hours at 20-30 ℃, adding 1.7g of sodium borohydride acetate into the crude product, and stirring for 18 hours to perform a central control reaction, wherein TLC is free from raw materials; adding saturated sodium bicarbonate aqueous solution into the reaction system until the pH value is 7-8, standing for layering, and adding 10mL of ethyl acetate for extracting a water phase; the organic phases were combined, washed once with 3mL of saturated brine, the organic phase concentrated to dryness, crude column chromatography (DCM/meoh=20:1 elution) to give compound 3D:1.2g of a colorless oil; yield in two steps: 85.1%.1H NMR (400 MHz, CDCl) 3 )δ8.02(s,1H),7.27(s,1H),7.03-7.01(d,J＝8.0Hz,1H),6.46(brs,1H),6.40-6.38(d,J＝8.0Hz,1H),5.24-5.22(m,1H),4.61-4.38(m,2H),3.84(s,3H),3.81(s,3H),3.71-3.68(dd,J＝12.0Hz,1H),3.50-3.47(dd,J＝12.0Hz,1H),2.55-2.53(m,1H),2.30(s,3H),2.31-2.27(m,1H),2.12-2.07(m,2H),1.41-1.37(t,J＝8.0Hz,3H),0.93-0.91(d,J＝8.0Hz,3H),0.79-0.78(d,J＝4.0Hz,3H)。ESI m/z C 22 H 32 N 2 O 5 S[M+H]Calculated 437.2, measured 437.2.
Example 4:
synthesis of compound a:
r is selected from C1-C6 fatty alkyl, preferably methyl, ethyl, propyl, isopropyl or butyl, most preferably methyl;
r' is selected from methyl or ethyl;
ar is selected from phenyl or substituted phenyl, and the substituted phenyl is selected from p-methoxyphenyl, p-nitrobenzyl, 2, 4-dimethoxybenzyl and the like.
Hydrogenation reaction to remove Bn is exemplified:
1.0g of Compound 2D was dissolved in 10mL of ethanol, and 0.3g of 10% Pd/C was added to replace hydrogen; stirring at room temperature for reaction, and finishing central control; filtration, concentration of the filtrate to dryness, column chromatography (DCM/meoh=10:1 elution) afforded compound a as a pale yellow solid: 0.7g, yield: 91%.1H NMR (400 MHz, CD) 3 OD)δ8.38(s,1H),5.22-5.19(m,1H),4.44-4.39(m,2H),2.83-2.81(m,1H),2.60(s,3H),2.13-2.08(m,3H),1.44-1.40(t,3H),0.99-0.98(d,6H)。
The oxidation reaction DMB removal is exemplified:
dissolving 1.0g of compound 3D in 20mL of acetonitrile/water (1:1 volume ratio), adding 1.24g of potassium persulfate, heating to 65-70 ℃ and stirring for reaction for 2 hours, wherein the medium control conversion is complete; cooling to room temperature, concentrating the reaction solution, adding ethyl acetate for extraction, concentrating the organic phase to dryness, and performing column chromatography (DCM/MeOH=10:1 elution) to obtain a pale yellow solid compound A:0.5g, yield: 76%.
TFA acid DMB is exemplified:
2.0g of compound 3D is dissolved in 20mL of trifluoroacetic acid, the temperature is raised to reflux and stirring is carried out for 50 hours, and the central control reaction is completed; cooling to room temperature, concentrating the reaction solution, adding 10mL of ethyl acetate, adjusting pH to 7-8 with saturated sodium bicarbonate aqueous solution, standing, and layering; the aqueous phase was extracted once more with 10mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the mother liquor concentrated to dryness and separated by column chromatography (DCM/meoh=10:1 elution) to give compound a as a pale yellow solid: 1.1g, yield: 84%.
Comparative examples:
1.0g of Compound B was added to 10mL of THF and 1mL of 37% aqueous formaldehyde solution and stirred at 20-30℃for 3 hours, then 1.7g of sodium borohydride acetate was added and the reaction was controlled by stirring for 18 hours, and HPLC data showed Compound B: compound E=12.7/19.0/66.1.
The above description is only a preferred embodiment of the present invention, but the protection scope of the present invention is not limited thereto;
any person skilled in the art should, within the scope of the present disclosure, cover all equivalent substitutions or modifications according to the technical solution of the present invention and the inventive concept thereof.
Claims (11)
1. A synthetic method of the compound A comprises the following synthetic routes:
r is selected from H or fatty alkyl of C1-C6;
r' is selected from methyl or ethyl;
ar is selected from p-methoxyphenyl, p-nitrophenylmethyl or 2, 4-dimethoxybenzyl;
the method comprises the following steps:
s1: taking a compound B as a raw material, and carrying out reductive amination reaction with ArCHO to obtain a compound C;
s2: then carrying out reductive amination reaction with RCHO to obtain a compound D;
s3: the compound D is subjected to deprotection reaction to obtain a compound A;
the step S3 deprotection reaction is selected from oxidation deprotection reaction;
the oxidative deprotection reaction is carried out under the action of an oxidant, wherein the oxidant is selected from potassium persulfate.
2. The synthesis method according to claim 1, wherein: r is selected from methyl, ethyl, propyl, isopropyl or butyl.
3. The synthesis method according to claim 1, wherein: the reaction solvent of step S1 or step S2 is selected from DCM, THF, acetonitrile, toluene or methanol.
4. A synthetic method according to claim 3, characterized in that: the reaction solvent is selected from DCM or THF.
5. The synthesis method according to claim 1, wherein: the reductive amination of step S1 or step S2 uses a reducing agent selected from NaBH (OAc) 3 ，NaBH 4 ，NaBH 3 CN or Et 3 SiH。
6. The synthesis method according to claim 1, wherein: step S1 or step S2 is carried out at a reaction temperature of 0 to 50 ℃.
7. The method of synthesis according to claim 6, wherein: the reaction temperature is selected from 20-30 ℃.
8. The synthesis method according to claim 1, wherein: the oxidative deprotection reaction is carried out in acetonitrile, ethanol, THF or water.
9. The synthesis method according to claim 1, wherein: the oxidation deprotection reaction is carried out at the reaction temperature of 20-100 ℃.
10. The method of synthesis according to claim 9, wherein: the reaction temperature is selected from 65-70 ℃.
11. A process for preparing Tubulysin comprising the synthetic method of any one of claims 1 to 10.
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| WO2019144805A1 (en) * | 2018-01-25 | 2019-08-01 | 四川科伦博泰生物医药股份有限公司 | Substituted phenylethylamine compound and preparation method and use thereof |
Non-Patent Citations (4)
| Title |
|---|
| Andrew W. Patterson, et al.Expedient Synthesis of N-Methyl Tubulysin Analogues with High Cytotoxicity.《J. Org. Chem.》.2008,第第73卷卷第4362–4369页. * |
| Shekaraiah Devari, et al.Visible light-promoted C-H functionalization of ethers and electron-deficient arenes.《 Chem. Commun.》.2015,第第52卷卷第1490-1493页. * |
| Sushovan Paladhi, et al.Asymmetric Aldol Reaction of Thiazole-Carbaldehydes: Regio- and Stereoselective Synthesis of Tubuvalin Analogues.《Adv. Synth. Catal.》.2014,第第356卷卷第3370-3376页. * |
| 姚其正.《药物合成反应》.中国医药科技出版社,2019,(第第2版版),第433-434页. * |
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