CN110776527A - Preparation method of bortezomib intermediate - Google Patents

Abstract

The invention discloses a preparation method of a bortezomib intermediate. Firstly, dropwise adding isobutyl lithium into isopropoxy pinacol borate to prepare 2-methylpropyl pinacol borate, and then carrying out a homologation reaction (using LDA and zinc chloride), a substitution reaction (using hexamethyldisilazane-based lithium amide) and a salt forming reaction with hydrochloric acid to prepare (R) -1-amino-3-methylbutyl pinacol borate hydrochloride. The method has the advantages of easily obtained raw materials, simple and convenient operation, safety, environmental protection and high product yield, and is suitable for industrial production.

Description

Preparation method of bortezomib intermediate

Technical Field

The invention relates to a preparation method of a bortezomib intermediate, belonging to the technical field of organic synthesis.

Background

Bortezomib (Bortezomib), the first proteasome inhibitor to be used clinically. Bortezomib was approved by the FDA for the treatment of relapsed, refractory myeloma in 5 months of 2003, and was approved for marketing in the uk in 5 months of 2004 and in china in 9 months of 2005. Bortezomib in combination with melphalan and prednisone (MP regimen) for the treatment of multiple myeloma patients who have not been treated before and who are not amenable to high dose chemotherapy and myelosuppression; or a single agent for the treatment of multiple myeloma patients who relapse after receiving at least one or more treatments.

The (R) -1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride is a key intermediate in the preparation process of bortezomib, reacts with N- (2-pyrazinecarbonyl) -L-phenylalanine to prepare the bortezomib, and has wide market prospect.

The synthesis route of (R) -1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride mainly comprises the following two routes:

scheme 1: the method is characterized in that dichloromethylboronic acid is used as a raw material to perform esterification reaction with pinacol, then the dichloromethylboronic acid and isobutylmagnesium bromide form a complex, and the complex is rearranged, substituted and salified to obtain the dichloromethylboronic acid.

Scheme 2: preparing R-3-methyl-N- ((R) -1-tert-butylsulfinyl) -1-amino-butyl-pinacol borate by taking N-isoamyl-tert-butylsulfinylimine and pinacol diboron as raw materials under the action of a chiral catalyst ((ICy) CuOt-Bu), and hydrolyzing and removing tert-butylsulfinyl under acidic conditions to form salt, such as CN104860975A, (R) -1-amino-3-methylbutyl pinacol borate hydrochloride. The chiral catalyst used in the method is not easy to purchase and cannot be produced in batches.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a preparation method of a bortezomib intermediate. Firstly, dripping isobutyl lithium into isopropoxy pinacol borate to prepare 2-methylpropyl pinacol borate, and then carrying out homologous reaction, substitution and salt forming reaction to prepare (R) -1-amino-3-methylbutyl pinacol borate hydrochloride. The method has the advantages of easily obtained raw materials, simple and convenient operation, safety, environmental protection and high product yield, and is suitable for industrial production.

The technical scheme of the invention is as follows: a preparation method of a bortezomib intermediate ((R) -1-amino-3-methylbutylboronic acid pinacol ester hydrochloride) is characterized in that,

1) dropwise adding isobutyl lithium into isopropoxy pinacol borate, and reacting at-10 ℃ to obtain 2-methylpropyl pinacol borate (compound I);

2) dissolving 2-methylpropyl pinacol borate in an organic solvent, adding dichloromethane, cooling to below-50 ℃, dropwise adding Lithium Diisopropylamide (LDA), adding zinc chloride, and performing a homologation reaction to obtain a compound II;

3) carrying out substitution reaction on the compound II and hexamethyldisilazane lithium amide to obtain a compound III;

4) salifying the compound III with hydrochloric acid to obtain (R) -1-amino-3-methylbutylboronic acid pinacol ester hydrochloride (compound IV).

Preferably, steps 1) and 2) are protected with nitrogen.

Preferably, the solvent adopted in the step 1) is n-hexane, the dripping temperature of the isobutyl lithium is preferably-10 ℃ to-5 ℃, and the reaction time is 2-5 h. The molar ratio of the isopropoxyboronic acid pinacol ester to the isobutyllithium was 1: 1.0 to 2.0.

Preferably, the organic solvent adopted in the step 2) is THF, and the volume ratio of THF to dichloromethane is 8-12: 1, preferably 10: 1. the reaction time is 0.5-2 h. The mol ratio of the 2-methylpropylboronic acid pinacol ester to the lithium diisopropylamide to the zinc chloride is 1: 1-1.5: 2 to 5.

Preferably, the solvent used in step 3) is THF. The reaction temperature is-10 ℃ to 0 ℃. The reaction time is 1-2 h. The molar ratio of the compound II to the lithium hexamethyldisilazide is 1: 1 to 1.5.

Preferably, the solvent of step 4) is isopropyl ether. The reaction temperature is-10 ℃ to 5 ℃. The reaction time is 0.5-2 h.

The method specifically comprises the following steps:

1) under the protection of nitrogen, controlling the temperature to be-10 ℃, slowly dripping isobutyl lithium into a normal hexane solution of isopropoxy pinacol borate, stirring for reaction, washing and layering with water, extracting with normal hexane, combining normal hexane layers, drying and concentrating to obtain 2-methylpropyl pinacol borate;

2) under the protection of nitrogen, dissolving 2-methylpropyl pinacol borate in tetrahydrofuran, adding dichloromethane, cooling to below-50 ℃, dropwise adding lithium diisopropylamide, adding a tetrahydrofuran solution of zinc chloride after dropwise adding, after the reaction is finished, pickling, drying and concentrating;

3) dissolving the concentrated oil in tetrahydrofuran, cooling to-10-0 ℃, adding lithium hexamethyldisilazide, concentrating after the reaction is finished, pulping by using normal hexane, filtering and concentrating;

4) dissolving the concentrated oil in isopropyl ether, cooling to-10-5 ℃, adding hydrochloric acid, filtering after the reaction is finished, and drying to obtain (R) -1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride.

The invention has the beneficial effects that: the method has the advantages of easily obtained raw materials, simple and convenient operation, safety, environmental protection and high product yield (more than or equal to 68 percent), and is suitable for industrial production.

Detailed Description

The following examples are further illustrative of the present invention, but the present invention is not limited thereto.

Example 1:

1) dissolving 18.6g of isopropoxyboric acid pinacol ester into 100ml of n-hexane in a four-mouth reaction bottle, stirring, cooling to-10 to-5 ℃ under the protection of nitrogen, slowly dropwise adding 100ml of isobutyl lithium (1.2mol/L), stirring for reacting for 3 hours, washing 100ml of purified water for layering, extracting a water layer once by 100ml of n-hexane, combining n-hexane layers, drying and concentrating to obtain 15.6g of 2-methylpropyl boric acid pinacol ester;

2) under the protection of nitrogen, dissolving 15.6g of 2-methylpropyl pinacol borate in 100ml of tetrahydrofuran, adding 10ml of dichloromethane, cooling to below-50 ℃, dropwise adding 45ml of LDA (2M), adding 100ml of zinc chloride tetrahydrofuran solution (2M) after dropwise adding, keeping the temperature for reacting for 1 hour, washing with 100ml of 10% sulfuric acid after the reaction is finished, drying and concentrating;

3) dissolving the above concentrated oil in 100ml tetrahydrofuran, cooling to-5 deg.C, adding 80ml lithium hexamethyldisilazide (1M), reacting for 1.5 hr under heat preservation, concentrating, pulping with 100ml n-hexane, filtering, and concentrating;

4) dissolving the concentrated oil in 140ml of isopropyl ether, cooling to 0 ℃, adding 10ml of concentrated hydrochloric acid, preserving heat for reaction for 1 hour, filtering after the reaction is finished, and drying to obtain 18.1g of (R) -1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride (total yield is 72.5%).

Example 2:

1) dissolving 18.6g of isopropoxyboronic acid pinacol ester into 100ml of n-hexane in a four-mouth reaction bottle, stirring, cooling to 0-5 ℃ under the protection of nitrogen, slowly dropwise adding 100ml of isobutyllithium (1.2mol/L), stirring for reaction for 3 hours, washing 100ml of purified water for layering, extracting the water layer once by 100ml of n-hexane, combining the n-hexane layers, drying and concentrating to obtain 14.7g of 2-methylpropylboronic acid pinacol ester;

2) under the protection of nitrogen, dissolving 14.7g of 2-methylpropyl pinacol borate in 100ml of tetrahydrofuran, adding 10ml of dichloromethane, cooling to below-70 ℃, dropwise adding 42ml of LDA (2M), adding 100ml of zinc chloride tetrahydrofuran solution (2M) after dropwise adding, keeping the temperature for reacting for 1 hour, washing with 100ml of 10% sulfuric acid after the reaction is finished, drying and concentrating;

3) dissolving the above concentrated oil in 100ml tetrahydrofuran, cooling to-5 deg.C, adding 80ml lithium hexamethyldisilazide (1M), reacting for 1.5 hr under heat preservation, concentrating, pulping with 100ml n-hexane, filtering, and concentrating;

4) dissolving the concentrated oil in 140ml of isopropyl ether, cooling to 0 ℃, adding 10ml of concentrated hydrochloric acid, preserving heat for reaction for 1 hour, filtering after the reaction is finished, and drying to obtain 17.1g of (R) -1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride (total yield is 68.6%).

Example 3:

1) dissolving 18.6g of isopropoxyboronic acid pinacol ester into 100ml of n-hexane in a four-mouth reaction bottle, stirring, cooling to-10 to-5 ℃ under the protection of nitrogen, slowly dropwise adding 150ml of isobutyllithium (1.2mol/L), stirring for reacting for 3 hours, washing 100ml of purified water for layering, extracting a water layer once by 100ml of n-hexane, combining n-hexane layers, drying and concentrating to obtain 16.2g of 2-methylpropylboronic acid pinacol ester;

2) under the protection of nitrogen, 16.2g of 2-methylpropyl pinacol borate is dissolved in 100ml of tetrahydrofuran, 10ml of dichloromethane is added, the temperature is reduced to below minus 50 ℃, 45ml of LDA (2M) is dropwise added, 100ml of tetrahydrofuran solution (2M) of zinc chloride is added after the dropwise addition, the heat preservation reaction is carried out for 1 hour, and after the reaction is finished, 100ml of 10 percent sulfuric acid is used for washing, drying and concentrating;

3) dissolving the above concentrated oil in 100ml tetrahydrofuran, cooling to-5 deg.C, adding 80ml lithium hexamethyldisilazide (1M), reacting for 1.5 hr under heat preservation, concentrating, pulping with 100ml n-hexane, filtering, and concentrating;

4) dissolving the concentrated oil in 140ml of isopropyl ether, cooling to 0 ℃, adding 10ml of concentrated hydrochloric acid, preserving heat for reaction for 1 hour, filtering after the reaction is finished, and drying to obtain 19.1g of (R) -1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride (total yield is 76.6%).

Claims (8)

1. A preparation method of a bortezomib intermediate, wherein the intermediate is (R) -1-amino-3-methylbutylboronic acid pinacol ester hydrochloride, is characterized in that,

1) dropwise adding isobutyl lithium into isopropoxy pinacol borate, and reacting at-10 ℃ to obtain 2-methylpropyl pinacol borate;

2) dissolving 2-methylpropyl pinacol borate in an organic solvent, adding dichloromethane, cooling to below-50 ℃, dropwise adding lithium diisopropylamide, adding zinc chloride, and performing homologation reaction to obtain a compound II;

3) carrying out substitution reaction on the compound II and hexamethyldisilazane lithium amide to obtain a compound III;

4) salifying the compound III with hydrochloric acid to obtain (R) -1-amino-3-methylbutylboronic acid pinacol ester hydrochloride;

2. the method for preparing bortezomib intermediate according to claim 1, wherein steps 1) and 2) are protected by nitrogen.

3. The method for preparing bortezomib intermediate as claimed in claim 1, wherein n-hexane is used as solvent in step 1).

4. The method for preparing a bortezomib intermediate as claimed in claim 1, wherein the temperature of dropwise addition of isobutyllithium in step 1) is from-10 ℃ to-5 ℃.

5. The method for preparing a bortezomib intermediate according to claim 1, wherein the organic solvent used in step 2) is tetrahydrofuran, and the volume ratio of tetrahydrofuran to dichloromethane is 8-12: 1.

6. the method for preparing a bortezomib intermediate as claimed in claim 1, wherein the solvent used in step 3) is tetrahydrofuran, and the reaction temperature is-10 ℃ to 0 ℃.

7. The method for preparing a bortezomib intermediate as claimed in claim 1, wherein the solvent used in step 4) is isopropyl ether, and the reaction temperature is-10 ℃ to 5 ℃.

8. The process for producing a bortezomib intermediate as claimed in any one of claims 1 to 7,

1) under the protection of nitrogen, controlling the temperature to be-10 ℃, slowly dripping isobutyl lithium into a normal hexane solution of isopropoxy pinacol borate, stirring for reaction, washing and layering with water, extracting with normal hexane, combining normal hexane layers, drying and concentrating to obtain 2-methylpropyl pinacol borate;

2) under the protection of nitrogen, dissolving 2-methylpropyl pinacol borate in tetrahydrofuran, adding dichloromethane, cooling to below-50 ℃, dropwise adding lithium diisopropylamide, adding a tetrahydrofuran solution of zinc chloride after dropwise adding, after the reaction is finished, pickling, drying and concentrating;

3) dissolving the concentrated oil in tetrahydrofuran, cooling to-10-0 ℃, adding lithium hexamethyldisilazide, concentrating after the reaction is finished, pulping by using normal hexane, filtering and concentrating;

4) dissolving the concentrated oil in isopropyl ether, cooling to-10-5 ℃, adding hydrochloric acid, filtering after the reaction is finished, and drying to obtain (R) -1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride.