CN110776527A - Preparation method of bortezomib intermediate - Google Patents
Preparation method of bortezomib intermediate Download PDFInfo
- Publication number
- CN110776527A CN110776527A CN201911211987.0A CN201911211987A CN110776527A CN 110776527 A CN110776527 A CN 110776527A CN 201911211987 A CN201911211987 A CN 201911211987A CN 110776527 A CN110776527 A CN 110776527A
- Authority
- CN
- China
- Prior art keywords
- reaction
- tetrahydrofuran
- bortezomib
- pinacol borate
- concentrating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 20
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- -1 2-methylpropyl pinacol borate Chemical compound 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 7
- 239000011592 zinc chloride Substances 0.000 claims abstract description 7
- WULZFOSYFJWKOH-UHFFFAOYSA-N B(O)(O)O.C(C)(C)OCC(O)(C)C(C)(C)O Chemical compound B(O)(O)O.C(C)(C)OCC(O)(C)C(C)(C)O WULZFOSYFJWKOH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 238000007163 homologation reaction Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 19
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 7
- AWYDETVSHIINIW-ZSCHJXSPSA-N OC(C)(C)C(C)(C)O.N[C@@H](CC(C)C)B(O)O Chemical compound OC(C)(C)C(C)(C)O.N[C@@H](CC(C)C)B(O)O AWYDETVSHIINIW-ZSCHJXSPSA-N 0.000 claims description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 5
- 238000004537 pulping Methods 0.000 claims description 5
- ADICRSVFBDCOLO-FVGYRXGTSA-N (1r)-3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-1-amine;hydrochloride Chemical group Cl.CC(C)C[C@H](N)B1OC(C)(C)C(C)(C)O1 ADICRSVFBDCOLO-FVGYRXGTSA-N 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- MXJGZAMERDEUKM-UHFFFAOYSA-N N[Li].C[Si](N[Si](C)(C)C)(C)C Chemical compound N[Li].C[Si](N[Si](C)(C)C)(C)C MXJGZAMERDEUKM-UHFFFAOYSA-N 0.000 claims description 2
- 238000005554 pickling Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 abstract 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 abstract 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000004321 preservation Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- FHQMPOBQBLDZJE-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-(2-methylpropyl)-1,3,2-dioxaborolane Chemical compound CC(C)CB1OC(C)(C)C(C)(C)O1 FHQMPOBQBLDZJE-UHFFFAOYSA-N 0.000 description 3
- MRWWWZLJWNIEEJ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane Chemical compound CC(C)OB1OC(C)(C)C(C)(C)O1 MRWWWZLJWNIEEJ-UHFFFAOYSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- DKRMKJKQCXCUGJ-UHFFFAOYSA-N dichloromethylboronic acid Chemical compound OB(O)C(Cl)Cl DKRMKJKQCXCUGJ-UHFFFAOYSA-N 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HANCUBNDHABGSE-UHFFFAOYSA-L zinc;oxolane;dichloride Chemical compound [Cl-].[Cl-].[Zn+2].C1CCOC1 HANCUBNDHABGSE-UHFFFAOYSA-L 0.000 description 2
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- WHQHIIFNBWIJSG-UHFFFAOYSA-N C(C)(C)OOB(O)O.OC(C)(C)C(C)(C)O Chemical compound C(C)(C)OOB(O)O.OC(C)(C)C(C)(C)O WHQHIIFNBWIJSG-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- CMWBEISSZHZIMU-UHFFFAOYSA-M [Br-].CC(C)C[Mg+] Chemical group [Br-].CC(C)C[Mg+] CMWBEISSZHZIMU-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911211987.0A CN110776527A (en) | 2019-12-02 | 2019-12-02 | Preparation method of bortezomib intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911211987.0A CN110776527A (en) | 2019-12-02 | 2019-12-02 | Preparation method of bortezomib intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110776527A true CN110776527A (en) | 2020-02-11 |
Family
ID=69393975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911211987.0A Pending CN110776527A (en) | 2019-12-02 | 2019-12-02 | Preparation method of bortezomib intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110776527A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4537773A (en) * | 1983-12-05 | 1985-08-27 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid derivatives |
| US20120289733A1 (en) * | 2011-05-11 | 2012-11-15 | Anderson Development Company | Novel borate derivatives and their applications |
| CN102803271A (en) * | 2009-06-19 | 2012-11-28 | 力奇制药公司 | Process for hydrogenation of halogenoalkenes without dehalogenation |
| CN103304629A (en) * | 2013-06-26 | 2013-09-18 | 江苏奥赛康药业股份有限公司 | Preparation method of high-optical purity bortezomib and intermediate of bortezomib |
| CN103408636A (en) * | 2013-08-23 | 2013-11-27 | 南京正大天晴制药有限公司 | Preparation method of bortezomib |
| CN103497233A (en) * | 2013-09-30 | 2014-01-08 | 哈药集团技术中心 | Preparation method for bortezomib |
-
2019
- 2019-12-02 CN CN201911211987.0A patent/CN110776527A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4537773A (en) * | 1983-12-05 | 1985-08-27 | E. I. Du Pont De Nemours And Company | α-Aminoboronic acid derivatives |
| CN102803271A (en) * | 2009-06-19 | 2012-11-28 | 力奇制药公司 | Process for hydrogenation of halogenoalkenes without dehalogenation |
| US20120289733A1 (en) * | 2011-05-11 | 2012-11-15 | Anderson Development Company | Novel borate derivatives and their applications |
| CN103304629A (en) * | 2013-06-26 | 2013-09-18 | 江苏奥赛康药业股份有限公司 | Preparation method of high-optical purity bortezomib and intermediate of bortezomib |
| CN103408636A (en) * | 2013-08-23 | 2013-11-27 | 南京正大天晴制药有限公司 | Preparation method of bortezomib |
| CN103497233A (en) * | 2013-09-30 | 2014-01-08 | 哈药集团技术中心 | Preparation method for bortezomib |
Non-Patent Citations (1)
| Title |
|---|
| MALGORZATA MYSLINSKA ET AL.: "Practical and efficient applications of novel dioxaborolanes and dioxaborinanes in the synthesis of corresponding boronates and their use in the palladium-catalyzed cross coupling reactions", 《TETRAHEDRON LETTERS》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104119367A (en) | Preparation method of aryl boric acid | |
| CN113999166B (en) | Synthesis method of tinib bulin | |
| US8765997B2 (en) | Process for preparing 4-borono-L-phenylalanine | |
| CN111153869B (en) | Method for preparing oxazole compound | |
| CN102731542B (en) | Preparation method of p-bromophenyl-boric acid | |
| CN110776527A (en) | Preparation method of bortezomib intermediate | |
| CN101863912A (en) | Preparation method of cyclopropylboronic acid | |
| EP2865682B1 (en) | Process for preparing 4-Borono-L-Phenylalanine | |
| CN103145746A (en) | Process method for synthesizing cyclopentene/ hexene-1-boronic acid pinacol cyclic ester | |
| CN113683527B (en) | Preparation method of trifloxystrobin | |
| CN104549506A (en) | Preparation method of aluminum-based catalyst for alkylation reaction | |
| CN105618135A (en) | Preparation method of chiral CBS catalyst | |
| CN103896984B (en) | The synthetic method of 3-methyl isophthalic acid-phenyl-1-phosphorus heterocycle penta-3-alkene-1-oxide compound | |
| CN112479991A (en) | Preparation method of 2-bromo-5-aldehyde pyridine | |
| CN108586525B (en) | Preparation method of n-hexyl phosphoric acid | |
| CN110903320A (en) | Preparation method of benfotiamine intermediate phosphorothioamine | |
| CN111393314A (en) | Process for preparing 2-alkyl-2-aminopropionate hydrochloride | |
| CN102850384A (en) | Synthesizing of 4-chloro-7-methoxyindole-2-boric acid | |
| CN111533656A (en) | Synthesis method of tert-butyl 4-methoxy-3-oxobutyrate | |
| JP2016517897A (en) | Aminoaryl-boronic acids and esters and methods for producing aminoheteroaryl boronic acids and esters | |
| CN103435634B (en) | A kind of preparation method of hexyllithium | |
| CN109053780B (en) | Preparation method of antitumor drug Acalabrutinib key intermediate | |
| CN112778089B (en) | New synthetic method of 4, 4-trifluoro-1-butanol and homologs thereof | |
| JP4118682B2 (en) | Process for producing formylphenylboronic acid | |
| CN111393256B (en) | Synthetic method of 2,2',3,3',5,5',6,6' -octafluoro-4,4 ' -dibromobiphenyl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200211 |
|
| RJ01 | Rejection of invention patent application after publication |