CN103787956A - Preparation method of midbody for preparing pomalidomide - Google Patents
Preparation method of midbody for preparing pomalidomide Download PDFInfo
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- CN103787956A CN103787956A CN201410025007.9A CN201410025007A CN103787956A CN 103787956 A CN103787956 A CN 103787956A CN 201410025007 A CN201410025007 A CN 201410025007A CN 103787956 A CN103787956 A CN 103787956A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 title abstract description 4
- 229960000688 pomalidomide Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract description 6
- -1 2,6-dioxo-3-piperidyl Chemical group 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 5
- 229940124660 anti-multiple myeloma Drugs 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000005711 Benzoic acid Substances 0.000 abstract 1
- 235000010233 benzoic acid Nutrition 0.000 abstract 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 238000001514 detection method Methods 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- 238000004845 hydriding Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 8
- 101150065749 Churc1 gene Proteins 0.000 description 8
- 102100038239 Protein Churchill Human genes 0.000 description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 208000034578 Multiple myelomas Diseases 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 210000004180 plasmocyte Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 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 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 229940099039 velcade Drugs 0.000 description 2
- YCPULGHBTPQLRH-UHFFFAOYSA-N 3-aminopiperidine-2,6-dione;hydron;chloride Chemical compound Cl.NC1CCC(=O)NC1=O YCPULGHBTPQLRH-UHFFFAOYSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000002774 Paraproteinemias Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000010626 plasma cell neoplasm Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation method of a midbody for preparing anti-multiple myeloma pomalidomide. The preparation method comprises the following steps: dissolving a compound as shown in a formula III in a solvent, reducing by using hydrogen in the existence of a palladium carbon catalyst, and then collecting a compound as shown in a formula IV from a reaction product, the compound as shown in the formula IV is the midbody, namely 3-amion-[(2,6-dioxo-3-piperidyl) carbamoyl group] benzoic acid and esters thereof for preparing the pomalidomide. The preparation method has the advantages that reaction steps are few, conditions are mild, the aftertreatment is simple, the yield is high, the preparation method is suitable for large-scale industrial production, and the reaction formula is as shown in descriptions.
Description
Technical field
The present invention relates to the preparation method for the preparation of anti-multiple myeloma medicine pool horse degree amine intermediate, be specifically related to the preparation method of 3-amino-[(2,6-dioxo-3-piperidyl) formamyl] phenylformic acid and ester thereof.
Background technology
Multiple myeloma (MM) is a kind of the malignant plasma cell dyscrasia, its tumour cell originates from the plasmocyte in marrow, and the cell of plasmocyte to be bone-marrow-derived lymphocyte grow final function phases, WHO is classified as the one of B cell lymphoma at present, is called plasma cell myeloma/plasmoma.It is characterized by marrow plasmocyte paraplasm and excessively generate with monoclonal immunoglobulin or light chain (M albumen), and only a few patient can be the not secretor type MM that does not produce M albumen.Multiple myeloma is often with multiple molten bone infringement, hypercalcemia, anaemia, kidney damage.Because the generation of normal immunoglobulin (Ig) is suppressed, therefore easily there are various bacterial infections.Sickness rate is estimated as 2～3,/10 ten thousand, and M-F is 1.6:1, mostly patient age >40 year.
At present, the drug main for the treatment of multiple myeloma will comprise: Velcade, card coffee assistant rice and pool horse degree amine etc., and wherein to moor horse degree amine and be mainly used in the patient to Velcade generation resistance, curative effect is better.
Pool horse degree amine (Pomalidomide), chemistry 3-amino-(2 by name, 6-dioxo-3-piperidyl)-phthalic imidine, that a kind of oral immunity of being researched and developed by Celege company regulates antitumor drug, obtaining FDA approval in 2013.2.8 goes on the market in the U.S., be used for the treatment of transitivity Refractory Multiple Myeloma, clinical form is racemic mixture.
3-amino-[(2,6-dioxo-3-piperidyl) formamyl] phenylformic acid and ester thereof are the key intermediates of preparation pool horse degree amine, and structure is as follows:
Described 3-amino-[(2; 6-dioxopiperidine-3-yl) formamyl] phenylformic acid and ester cpds thereof; in patent WO2008/007979A1, report, but the document is not set forth the synthetic method of particular compound, also do not have other documents to report its synthetic method.
Summary of the invention
The object of this invention is to provide a kind of preparation method of the intermediate for the preparation of pool horse degree amine, to meet the needs of association area development.
The preparation method of the intermediate for the preparation of pool horse degree amine provided by the invention, comprises the steps:
Compound shown in formula III is dissolved in solvent, under the existence of palladium-carbon catalyst, hydrogen reducing, then the compound shown in collection type IV from reaction product, be described intermediate 3-amino-[(2,6-dioxopiperidine-3-yl) formamyl] phenylformic acid and ester thereof for the preparation of pool horse degree amine;
Wherein, described solvent is the conventional organic solvent in this area, more than one in particular methanol, ethanol, Virahol, acetone, ethyl acetate, tetrahydrofuran (THF), acetonitrile or toluene;
Solvent load be for making reaction normally, preferably with the scope that is 15～200mL/g of the compound volume mass ratio shown in formula III; More preferably with the scope that is 50～100mL/g of the compound volume mass ratio shown in formula III;
Described palladium-carbon catalyst is the catalyzer that this area is usually used in hydro-reduction reaction, preferably uses 5% or 10% specification, and wherein percentage ratio is massfraction;
Hydrogen reaction pressure is 0.1～5.0MPa, preferably under 0.5～2.0MPa condition, reacts;
The quality of palladium carbon is hydro-reduction catalytic amount conventional in this area, is preferably 1%～50% of intermediate III quality, more preferably 5%～10% of intermediate III quality;
The temperature of described hydro-reduction reaction is conventional reduction temperature of reaction, preferably 5～100 ℃, more preferably under 10～60 ℃ of conditions, reacts; The process of described reaction can be monitored by TLC or HPLC, generally react completely as reaction end using intermediate III, in order further to obtain the intermediate IV that purity is higher, mainly carrying out after completion of the reaction following last handling process: filter, concentrate, be dried;
Reaction expression is as follows:
Wherein:
R represents H, CH
3, C
2h
5or C
3h
7;
Compound shown in described formula III is reported in patent WO2008/007979A1.The present invention adopts and prepares with the following method III-1, III-2, III-3, III-4, and reaction formula is shown below.
The present invention is raw materials used all to be had commercially available with reagent;
Content of the present invention has no report, it is advantageous that: raw material is easy to get, and reactions steps is few, mild condition, and aftertreatment is simple, and yield is high, is applicable to large-scale industrial production.
Embodiment
Mode by following embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in described embodiment, according to ordinary method and condition, or selects according to catalogue.
Embodiment 1
The preparation of compound III-1, wherein R is H;
3-nitrophthalic acid acid anhydride (I, 44.0g, 0.23mol), 3-amino-2,6-dioxopiperidine hydrochloride (II, 37.9g, 0.23mol), be dissolved in 600mL tetrahydrofuran (THF) (THF), then slowly in system, drip triethylamine (23.27 g, 0.23mol), hierarchy of control temperature <20 ℃ in the process of dropping, after dropwising, room temperature reaction 30min, filters THF(30mL × 3) washing leaching cake, vacuum-drying obtains intermediate III 67.20g, yield 91.0%.
1H-NMR(DMSO-D6)δ：1.88（-*CHC
H a H
bCH
cH
d-，1H，m），2.21（-*CHCH
aH
bC
H c H
d-，1H，m），2.53（-*CHCH
a H bCH
cH
d-，1H，m），2.72（-*CHCH
aH
bCH
c H d-，1H，m），4.74（-*
CHCH
aH
bCH
cH
d-，1H，m），7.76（-ArH，1H，t），8.16（-ArH，1H，d），8.18（-ArH，1H，d），8.99（-COOH，1H，d），10.85（-CO-NH-，1H，s），13.60（-CO-NH-CO-，1H，s）；ESI-MS(m/z)=322.03[M+H]
+。
Embodiment 2
Compound III-2, III-3, III-4th, prepared and obtain for raw material by compound III-1.
Compound III-2 preparation: wherein: R is CH
3
Compound III-1(32.16g, 0.10mol), methyl alcohol (3.84g, 0.12mol), be dissolved in 100mL methylene dichloride ice bath cooling, slowly in system, drip thionyl chloride (11.75g, 0.12mol), hierarchy of control temperature <5 ℃ in the process of dropping, after dropwising, be warming up to room temperature reaction 3.0 hours, after TLC detection reaction is complete, concentrated, in residue, add saturated sodium bicarbonate solution, there is solid to separate out, filter and obtain target product compound III-2,30.83g, 92%.
The preparation of compound III-3: wherein, R is C
2h
5
Compound III-1(32.16g, 0.10mol), ethanol (5.52g, 0.12mol), be dissolved in 100mL methylene dichloride ice bath cooling, slowly in system, drip thionyl chloride (11.75g, 0.12mol), hierarchy of control temperature <5 ℃ in the process of dropping, after dropwising, be warming up to room temperature reaction 3.0 hours, after TLC detection reaction is complete, concentrated, in residue, add saturated sodium bicarbonate solution, there is solid to separate out, filter and obtain target product compound III-3,32.47g, 93%.
The preparation of compound III-4: wherein, R is C
3h
7
Compound III-1(32.16g, 0.10mol), propyl alcohol (7.21g, 0.12mol), be dissolved in 100mL methylene dichloride ice bath cooling, slowly in system, drip thionyl chloride (11.75g, 0.12mol), hierarchy of control temperature <5 ℃ in the process of dropping, after dropwising, be warming up to room temperature reaction 3.0 hours, after TLC detection reaction is complete, concentrated, in residue, add saturated sodium bicarbonate solution, there is solid to separate out, filter and obtain target product compound III-4,34.28g, 94.4%.
Embodiment 3
The preparation of compounds Ⅳ-1
Compound III-1(32.10g, 0.10mol), 10%Pd/C(50%, 16.05g) and toluene (6.42L) join in hydriding reactor, be filled with the pressure of 0.1MPa, under 100 ℃ of conditions, react, after TLC detection reaction, filter, methanol wash (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 27.65g, yield 95.0%.
1H-NMR(DMSO-D
6)δ：1.89（-*CHC
H a H
bCH
cH
d-，1H，m），2.16（-*CHCH
aH
bC
H c H
d-，1H，m），2.51（-*CHCH
a H bCH
cH
d-，1H，m），2.78（-*CHCH
aH
bCH
c H d-，1H，m），4.65（-*
CHCH
aH
bCH
cH
d-，1H，m），5.51（-NH
2，2H，s），6.86（-ArH，1H，t），7.02（-ArH，1H，t），7.13（-ArH，1H，d），8.61（-COOH，1H，d），10.92（-CO-NH-，1H，s），13.62（-CO-NH-CO-，1H，s）；ESI-MS(m/z)=292.09[M+H]
+。
Embodiment 4
The preparation of compounds Ⅳ-1
Compound III-1(32.10g, 0.10mol), 10%Pd/C(1%, 0.32g) and ethanol (482mL) join in hydriding reactor, be filled with the pressure of 5.0MPa, under 5 ℃ of conditions, react, after TLC detection reaction, filter, washing with alcohol (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 27.35g, yield 94.0%.
Embodiment 5
The preparation of compounds Ⅳ-1
Compound III-1(32.10g, 0.10mol), 10%Pd/C(1%, 0.32g) and methyl alcohol (482mL) join in hydriding reactor, be filled with the pressure of 5.0MPa, under 5 ℃ of conditions, react, after TLC detection reaction, filter, washing with alcohol (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 27.35g, yield 94.0%.
Embodiment 6
The preparation of compounds Ⅳ-2
Compound III-2(33.51g, 0.10mol), 5%Pd/C(2%, 0.67g) and tetrahydrofuran (THF) (1.01L) join in hydriding reactor, be filled with the pressure of 4.0MPa, under 7 ℃ of conditions, react, after TLC detection reaction, filter, tetrahydrofuran (THF) washing (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 28.82g, yield 94.5%.
Embodiment 7
The preparation of compounds Ⅳ-2
Compound III-2(33.51g, 0.10mol), 10%Pd/C(5%, 1.68g) and Virahol (1.68L) join in hydriding reactor, be filled with the pressure of 2.0MPa, under 10 ℃ of conditions, react, after TLC detection reaction, filter, washed with isopropyl alcohol (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 29.71g, yield 97.4%.
Embodiment 8
The preparation of compounds Ⅳ-3
Compound III-3(34.91g, 0.10mol), 10%Pd/C(7%, 2.44g) and ethyl acetate (2.44L) join in hydriding reactor, be filled with the pressure of 1.5MPa, under 40 ℃ of conditions, react, after TLC detection reaction, filter, ethyl acetate washing (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 31.27g, yield 98.0%.
Embodiment 9
The preparation of compounds Ⅳ-3
Compound III-3(34.91g, 0.10mol), 10%Pd/C(7%, 2.44g) and acetone (2.44L) join in hydriding reactor, be filled with the pressure of 1.5MPa, under 40 ℃ of conditions, react, after TLC detection reaction, filter, ethyl acetate washing (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 31.27g, yield 98.0%.
Embodiment 10
The preparation of compounds Ⅳ-3
Compound III-3(34.91g, 0.10mol), 10%Pd/C(10%, 3.49g) and acetonitrile (3.49L) join in hydriding reactor, be filled with the pressure of 0.5MPa, under 60 ℃ of conditions, react, after TLC detection reaction, filter, acetonitrile washing (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 31.33g, yield 98.2%.
Embodiment 11
The preparation of compounds Ⅳ-4
Compound III-4(36.31g, 0.10mol), 10%Pd/C(20%, 7.26g) and n-propyl alcohol (5.45L) join in hydriding reactor, be filled with the pressure of 0.2MPa, under 80 ℃ of conditions, react, after TLC detection reaction, filter, washing with acetone (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 31.58g, yield 94.8%.
Embodiment 12
The preparation of compounds Ⅳ-4
Compound III-4(36.31g, 0.10mol), 10%Pd/C(20%, 7.26g) and solvent (n-propyl alcohol+acetonitrile, v/v=1:1,5.45L) join in hydriding reactor, be filled with the pressure of 0.2MPa, under 80 ℃ of conditions, react, after TLC detection reaction, filter, washing with acetone (20mL × 3), filtrate is concentrated, and vacuum-drying obtains compounds Ⅳ 31.58g, yield 94.8%.
Claims (7)
1. for the preparation of the preparation method of pool horse degree amine intermediate, it is characterized in that, comprise the steps:
Compound shown in formula III is dissolved in solvent, under the existence of palladium-carbon catalyst, through hydrogen reducing, the then compound shown in collection type IV from reaction product, compounds Ⅳ can be used as the key intermediate of preparation pool horse degree amine, and reaction formula is as follows:
2. method according to claim 1, is characterized in that, described solvent is more than one in methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, tetrahydrofuran (THF), acetonitrile or toluene.
3. method according to claim 1, is characterized in that, solvent load is and the scope that is 15～200mL/g of the compound volume mass ratio shown in formula III.
4. method according to claim 3, is characterized in that, solvent load is and the scope that is 50～100mL/g of the compound volume mass ratio shown in formula III.
5. according to the method described in claim 1～4 any one, it is characterized in that, the mass percent that described palladium-carbon catalyst is palladium is 5% or 10% palladium-carbon catalyst.
6. according to the method described in claim 1～4 any one, it is characterized in that, hydrogen reaction pressure is 0.1～5.0MPa, and the temperature of reduction reaction is 5～100 ℃.
7. according to the method described in claim 1～4 any one, it is characterized in that, the quality of palladium carbon is 1%～50% of intermediate III quality.
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|---|---|---|---|
| CN201410025007.9A CN103787956B (en) | 2014-01-20 | 2014-01-20 | For the preparation of the preparation method of the intermediate of pool horse degree amine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105334270A (en) * | 2014-06-30 | 2016-02-17 | 深圳海王药业有限公司 | Liquid chromatography for separating and determining pomalidomide intermediate related substance |
Citations (3)
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|---|---|---|---|---|
| WO2003014315A2 (en) * | 2001-08-06 | 2003-02-20 | The Children's Medical Center Corporation | Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs |
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| WO2008007979A1 (en) * | 2006-07-12 | 2008-01-17 | Auckland Uniservices Limited | (2,6-dioxo-3-piperinyl)amidobenzoic immunomodulatory and anti-cancer derivatives |
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| WO2003014315A2 (en) * | 2001-08-06 | 2003-02-20 | The Children's Medical Center Corporation | Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs |
| CN1720240A (en) * | 2002-10-09 | 2006-01-11 | 先灵公司 | Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands |
| WO2008007979A1 (en) * | 2006-07-12 | 2008-01-17 | Auckland Uniservices Limited | (2,6-dioxo-3-piperinyl)amidobenzoic immunomodulatory and anti-cancer derivatives |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105334270A (en) * | 2014-06-30 | 2016-02-17 | 深圳海王药业有限公司 | Liquid chromatography for separating and determining pomalidomide intermediate related substance |
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| CN103787956B (en) | 2016-03-30 |
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