WO2016061718A1 - Compound and preparation method therefor, and method for preparing maytansine dm1 - Google Patents

Abstract

The present invention relates to a compound, wherein a chemical structure of the compound is represented by (II), and R is selected from any one of ethyl, tert-butyl, methoxy acyl methyl and -(CH₂)_nOH (n=1, 2, 3, 4). The present invention also relates to a method for preparing the compound, and a method for preparing maytansine DM1 by using the compound as an intermediate. The method of the present invention has a moderate reaction condition, and the yield of maytansine DM1 reaches 91%.

Description

Compound, preparation method thereof and preparation method of maytansin DM1 Technical field

The invention relates to a preparation method of a compound, in particular to a preparation method of maytansine DM1 and a preparation method of an intermediate compound for preparing maytansin DM1.

Background technique

Kadcyla (ado-trastuzumabemtansine, (I)), an antibody drug conjugate developed by Roche Pharmaceuticals, coupled with trastuzumab and the small molecule microtubule inhibitor maytansin DM1 (II) for treatment HER-2 positive late metastatic breast cancer.

US6333410 discloses a process for preparing maytansin DM1 starting from anacin sp. P3 (abbreviated as AP3). The first step of the method is to obtain maytansinol by reductive hydrolysis reaction; the second step is to carry out esterification reaction of maytansinol with bis-indenyl N-methylalanine to obtain 100% epimerized dimercapto group intermediate The third step is column chromatography to obtain a bis-indenyl intermediate with C3 in the S configuration; the fourth step is followed by reduction to obtain maytansin DM1. In step 1, the oxidative hydrolysis of anacin C3 is carried out to obtain maytansinol. The most preferred reaction conditions are controlled under nitrogen gas, and the temperature is controlled between -37 ° C and -45 ° C for more than three hours, which is very large for the pilot synthesis. The inconvenience increases the production cost and limits the application of the method in production.

Summary of the invention

An object of the present invention is to provide a preparation method of maytansin DM1 having mild reaction conditions, an intermediate compound of maytansin DM1 and a preparation method thereof.

A compound whose chemical structural formula is as follows:

Wherein R is selected from the group consisting of ethyl, t-butyl, methoxymethylmethyl, and -(CH ₂ ) _n OH (n = 1, 2, 3, 4).

A method for preparing a compound, which comprises using AP3 as a raw material, using LiAl(t-BuO) ₃ H as a reducing agent to obtain maytansinol, and then a phenanthryl acid and a 5-benzyl glutamate N-carboxycyclolactone ( NCA) undergoes an esterification reaction, and reacts with the compound COOH(CH ₂ ) ₂ SSR in the presence of a condensing agent to obtain the following compound 1, wherein R is selected from the group consisting of ethyl, t-butyl, methoxyacylmethyl, -( CH ₂ ) _n OH (n = 1, 2, 3, 4), the reaction formula is:

A preparation method of maytansine DM1, which is prepared by the following compound 1 by reduction reaction,

Wherein R is selected from the group consisting of ethyl, t-butyl, methoxymethylmethyl, and -(CH ₂ ) _n OH (n = 1, 2, 3, 4).

In the method for preparing maytansin DM1 of the present invention, by using AP3 as a raw material and using LiAl(t-BuO) ₃ H as a reducing agent, maytansinol is obtained, so that the reaction process for producing maytansinol is milder, mayonidin DM1 The yield is as high as 91%.

detailed description

The following is a detailed description of the preparation method of the maytansin DM1 of the present invention and the intermediate compound of maytansin DM1 and a preparation method thereof.

In the following specific embodiments, nuclear magnetic resonance is measured by Bruker AMX-400 and INVOA-600 nuclear magnetic resonance spectroscopy, in which TMS is used as an internal standard, the chemical shift unit is ppm; and column chromatography is performed by Qingdao Ocean Chemical Plant. 300 mesh silica gel; TLC silica gel plate is HSGF-254 thin layer chromatography precast plate produced by Yantai Chemical Plant; petroleum ether boiling range is 60-90 °C.

A method for preparing maytansin DM1, comprising the steps of:

Step 1: Prepare maytansinol from AP3. Add 100 g of AP3 to the reaction flask equipped with a thermometer and a dropping funnel, then add 500 ml of anhydrous tetrahydrofuran to the reaction flask, and add LiAl at a concentration of 1 mol/L under nitrogen protection at -10 ° C to 10 ° C. -BuO) ₃ H tetrahydrofuran solution. After the dropwise addition of LiAl(t-BuO) ₃ H tetrahydrofuran solution, the reaction solution was controlled at -10 ° C to 10 ° C, stirred for 2 to 5 hours, and the reaction liquid was further cooled to 0 ° C to 4 ° C, and 150 ml of water was added dropwise. After the addition of water droplets, the reaction solution was stirred at a temperature of -10 ° C to 10 ° C for 30 minutes, and then 200 ml of an ethyl acetate solution containing 1% by weight of formic acid was added. After sufficient reaction, the white precipitate was removed by filtration. The filtrate was concentrated to give a white solid.m.

Step 2: Preparation of maytansin intermediate compound 1. The esterification reaction of maytansin with NCA is carried out by reacting with compound R-substituted 3-bismercaptopropionic acid in the presence of a condensing agent to obtain compound 1, wherein R is selected from the group consisting of ethyl, t-butyl, methoxymethylmethyl, -(CH ₂ ) _n OH(n=1,2,3,4), the reaction formula is:

Specifically, 120 g of maytansin prepared by the method of the first step was dissolved in 120 ml of anhydrous tetrahydrofuran and 6 mL of anhydrous DMF, and then 22 ml of N,N-diisopropylethylamine (DIPEA), 14 g of NCA and 200 g of three were added. Zinc fluoromethanesulfonate. The mixture was stirred at room temperature under nitrogen atmosphere for 15 to 40 hours, then 1 L of ethyl acetate and 1 L of saturated aqueous NaHCO _{3 was added} ; fractions; washed with saturated NaCl solution to remove ethyl acetate and then anhydrous MgSO. _4, dried and concentrated to give 150 g of crude product; 39 g of 3-(tert-butyldidecyl)propionic acid was dissolved in 600 mL of anhydrous DMF, and the above 150 g of crude product and 25 g of condensing agent 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride (EDCI) is added to the above 600 mL of anhydrous DMF solution, and the reaction solution is stirred at room temperature for 2 to 4 hours, and an appropriate amount of ethyl acetate and water are added for liquid separation, and the organic layer is saturated with NaHCO. _{3 The} solution was washed, washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution, and dried. The crude product was purified by column chromatography under a gradient of methanol/dichloromethane from 0% to 4% to give 27 g of compound 1 R = tert-butyl) as a white solid product. The white solid product is a maytansin intermediate compound whose nuclear magnetic data is:

1H NMR (400MHz, CHLOROFORM-d) d ppm 0.81 (s, 3H) 1.22 (s, 9H) 1.26-1.35 (m, 7H) 1.43-1.52 (m, 1H) 1.56 (d, J = 13.45 Hz, 1H) 1.65(s,3H)2.14-2.22(m,1H)2.57-2.70(m,2H)2.72-3.00(m,6H)3.01-3.14(m,2H)3.26(s,3H)3.37(s,3H) 3.45(brs,1H)3.41-3.54(m,1H)3.68(d,J=12.72Hz,1H)3.99(s,3H)4.28(t,J=10.51Hz,1H)4.78(dd,J=11.98, 2.93 Hz, 1H) 5.43 (d, J = 6.85 Hz, 1H) 5.66 (dd, J = 15.28, 8.93 Hz, 1H) 6.36 (s, 1H) 6.44 (dd, J = 15.28, 11.13 Hz, 1H) 6.65 ( s, 1H) 6.75 (d, J = 11.00 Hz, 1H) 6.79-6.87 (m, 1H).

Specifically, the condensing agent EDCI in step two is changed to N,N-dicyclohexylcarbodiimide (DCC), and 3-(tert-butyldidecyl)propionic acid is changed to 3-(methoxy acyl group). Condensation of propionic acid to obtain a maytansin intermediate compound of compound 1 having the following formula, the nuclear magnetic data of which is:

1H NMR (400MHz, CHLOROFORM-d) d ppm 0.81 (s, 3H) 1.28-1.35 (m, 10H) 1.44-1.52 (m, 1H) 1.58 (d, J = 13.20 Hz, 1H) 1.66 (s 3H) 2.20 (dd, J = 14.5, 3.06 Hz, 1H) 2.80 - 3.07 (m, 10H) 3.25 (s, 2H) 3.34 - 3.43 (m, 4H) 3.50 (s, 3H) 3.61-3.78 (m, 2H) 4.0 ( s,3H)4.13-4.22(m,2H)4.25-4.34(m,1H)4.73-4.89(m,1H)5.38-5.50(m,1H)5.61-5.72(m,1H)6.44(dd,J= 15.41, 11.25 Hz, 1H) 6.56-6.78 (m, 3H) 6.84 (s, 1H).

Further, by changing 3-(tert-butyldidecyl)propionic acid to 3-(ethyldidecyl)propionic acid without changing the condensing agent EDCI, Compound 1 wherein R is an ethyl group can be obtained, and 3- (tert-butyl-dimercapto-yl) propionic acid into 3- (hydroxymethyl-dimercapto-yl) propanoic acid compound can be prepared R 1 is a hydroxymethyl group, can be prepared accordingly R is (CH2) _n OH compound 1.

Step 3: Dissolve 8.6 g of Tris[2-carboxyethyl]phosphine hydrochloride (TCEP·HCl) in 50 mL of a 0.1 M/L potassium phosphate buffer solution (pH=7.4), and obtain 50 g of Compound 1 obtained in the previous step ( R = tert-butyl) dissolved in 150 mL of trifluoroethanol, added to the above potassium phosphate buffer solution, the reaction was stirred for 15 to 45 minutes, then concentrated most of the trifluoroethanol solution, the remaining reaction solution was added to 200 mL of ethyl acetate, and then used The organic layer was dried over anhydrous sodium sulfate and dried to give a white solid. Purification by column chromatography on a 0% to 4% gradient of alkane afforded 42 g of mayonidin DM1 with a yield of 91%.

The invention uses AP3 as a raw material and uses LiAl(t-BuO) ₃ H as a reducing agent to obtain maytansin, so that the reaction process for producing maytansinol is more mild, and the yield of maytansin DM1 is as high as 91%.

The specific embodiments of the present invention have been described in detail, and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and scope of the present invention are intended to be included within the scope of the present invention.

Claims (10)

A compound whose chemical structural formula is as follows:

Wherein R is selected from the group consisting of ethyl, t-butyl, methoxymethylmethyl, and -(CH ₂ ) _n OH (n = 1, 2, 3, 4). A method for preparing a compound, which comprises using AP3 as a raw material, using LiAl(t-BuO) ₃ H as a reducing agent to obtain maytansinol, and then a phenanthryl acid and a 5-benzyl glutamate N-carboxycyclolactone ( NCA) undergoes an esterification reaction, and reacts with the compound COOH(CH ₂ ) ₂ SSR in the presence of a condensing agent to obtain the following compound 1, wherein R is selected from the group consisting of ethyl, t-butyl, methoxyacylmethyl, -( CH ₂ ) _n OH (n = 1, 2, 3, 4), the reaction formula is:

The process for producing a compound according to claim 2, wherein the reaction temperature is -10 ° C to 10 ° C during the dropwise addition of LiAl(t-BuO) ₃ H. The method for preparing a compound according to claim 2, wherein the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), wherein R is selected Any one of ethyl, tert-butyl, -(CH ₂ ) _n OH (n = 1, 2, 3, 4). The method of preparing a compound according to claim 2, wherein the condensing agent is N,N-dicyclohexylcarbodiimide (DCC), wherein R is selected from the group consisting of ethyl, t-butyl, and -CH ₂ ) Any of _n OH (n = 1, 2, 3, 4). A preparation method of maytansine DM1, which is prepared by the following compound 1 by reduction reaction,

Wherein R is selected from the group consisting of ethyl, t-butyl, methoxymethylmethyl, and -(CH ₂ ) _n OH (n = 1, 2, 3, 4). The method of preparing the maytansinoid DM1 as claimed in claim 6, wherein: the AP3 as raw materials, LiAl (t-BuO) ₃ H to obtain a reducing agent maytansinol and maytansinol with (S) -3,4-dimethyloxazolidine-2,5-dione (NCA) undergoes esterification reaction, and reacts with compound COOH(CH ₂ ) ₂ SSR in the presence of a condensing agent to obtain the following compound 1, wherein R is selected from ethyl group, Any one of tert-butyl, methoxymethylmethyl, -(CH ₂ ) _n OH (n=1, 2, 3, 4), the reaction formula of which is:

The method for preparing maytansin DM1 according to claim 7, wherein the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride. Salt (EDCI) wherein R is selected from any of ethyl, tert-butyl, -(CH ₂ ) _n OH (n = 1, 2, 3, 4). The method for producing maytansine DM1 according to claim 7, wherein the condensing agent is N,N-dicyclohexylcarbodiimide (DCC), and R is a methoxymethylmethyl group. The method for producing maytansin DM1 according to claim 7, wherein the reaction temperature is -10 ° C to 10 ° C during the dropwise addition of LiAl(t-BuO) ₃ H.