CN1740160A - Synthesis process of loratadine intermediate - Google Patents
Synthesis process of loratadine intermediate Download PDFInfo
- Publication number
- CN1740160A CN1740160A CN 200510050742 CN200510050742A CN1740160A CN 1740160 A CN1740160 A CN 1740160A CN 200510050742 CN200510050742 CN 200510050742 CN 200510050742 A CN200510050742 A CN 200510050742A CN 1740160 A CN1740160 A CN 1740160A
- Authority
- CN
- China
- Prior art keywords
- loratadine
- chloro
- reaction
- ethyl
- pyridine
- 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
- 229960003088 loratadine Drugs 0.000 title claims abstract description 20
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title abstract description 6
- 230000015572 biosynthetic process Effects 0.000 title abstract 2
- 238000003786 synthesis reaction Methods 0.000 title abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001953 recrystallisation Methods 0.000 claims abstract description 9
- 239000012046 mixed solvent Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 229920000137 polyphosphoric acid Polymers 0.000 claims abstract description 5
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 14
- 125000000301 2-(3-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 13
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims description 8
- -1 suberyl Chemical group 0.000 claims description 7
- 238000010189 synthetic method Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 18
- 208000012839 conversion disease Diseases 0.000 abstract description 2
- JPCGKKFEDUHGDF-UHFFFAOYSA-N 3-[2-(3-chlorophenyl)ethyl]pyridine-2-carbonitrile Chemical compound ClC1=CC=CC(CCC=2C(=NC=CC=2)C#N)=C1 JPCGKKFEDUHGDF-UHFFFAOYSA-N 0.000 abstract 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 239000003208 petroleum Substances 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WBXZCDIZXWDPBL-UHFFFAOYSA-N 3-methylpyridine-2-carbonitrile Chemical compound CC1=CC=CN=C1C#N WBXZCDIZXWDPBL-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- DSPKXCZGSQZMRS-UHFFFAOYSA-N C(C1=CC=CC=C1)Cl.[Cl] Chemical compound C(C1=CC=CC=C1)Cl.[Cl] DSPKXCZGSQZMRS-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000003930 superacid Substances 0.000 description 2
- 239000004577 thatch Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The synthesis process of loratadine intermediate includes: adding P2O5 in 3-20 wt% into polyphosphoric acid ester through stirring at 175-240 deg.c to obtain homogeneous system; adding 3-[2-(3-chlorophenyl) ethyl]-2-pyridyl formonitrile in 4-16 wt% into the system and reaction at 175-240 deg.c for 5-14 hr to obtain the loratadine intermediate 8-chloro-5, 6-dihydro-11H-benzyo[5, 6]cycloheptyl[1, 2-b] pyridyl-11-tone; and re-crystallizing the intermediate with mixed solvent of ethyl acetate, n-hexane and petroleum in the volume ratio of 1 to 1 to 3. The present invention has mild reaction condition, simple operation, fast reaction speed, reaction conversion rate as high as 83.7-93.1 %, product yield of 62.9-78.2 %, product purity after re-crystallization of 98-99 %, and excellent industrial application foreground.
Description
Technical field
The present invention relates to a kind of Loratadine intermediate 8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-ketone synthetic method.
Background technology
Loratadine (loratadine), chemistry 4-(8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1 by name, 2-b] pyridine-11 alkene)-the 1-piperidine carboxylate, be oral long-acting tricyclic antidepressants antihistaminic, it is rapid-action, effect is strong, and the periphery histamine H1-receptor is had high selectivity, be [the DuBuske L M. of antihistamine drug of new generation of a kind of long-acting, no sedative effect, no anticholinergic effect, Clin Ther.1999,21 (2), 281～285].
About synthesizing of Loratadine, the synthetic method of bibliographical information mainly is to be raw material with 3-methyl-2-cyanopyridine, respectively by (1-methyl-4-piperidyl) [3-(2-(3-chloro-phenyl-)-ethyl-)-2-pyridyl]-ketone intermediate (1) and 8-chloro-5,6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11 ketone intermediate (2) comes synthetic.
Intermediate (1) synthetic is to be raw material with 3-methyl-2-cyanopyridine, through cyano protection, the highly basic effect down with the alkylation of a benzyl chloride chlorine, again through obtaining with the form reagent react behind the deprotection reduction generation cyano group; This intermediate (1) utilizes CH then
3SO
3H/BF
3, HF/BF
3Come cyclisation etc. different cyclization reagents, last and Vinyl chloroformate refluxes and obtains product Loratadine [Doris P.Schumacher, Bruce L.Murphy, Jon E.Clark, et al., J.org.Chem.1989,54,2242～2244].The sharpest edges of this route be the yield of reaction than higher, but with top CH
3SO
3H/BF
3, HF/BF
3When making cyclization reagent, owing to itself have intensive corrodibility, make and to use specific equipment such as Te Lilong aborning, and it is also bigger to the pollution of environment, thereby the industrial cost that improves, this makes it be subjected to certain restriction when concrete production, and under the very fierce situation of market competition now, this route obviously is uneconomic.This route has been used grignard reagent in reaction simultaneously, and this can increase the cost of condition control in the reaction.
Intermediate (2) synthetic also is to be raw material with 3-methyl-2-cyanopyridine, and through cyano protection, the highly basic effect down and the alkylation of a benzyl chloride chlorine; reduction generates the cyano group posthydrolysis through deprotection again, uses sulfur oxychloride [Cannata Vincenzo, Cotarca Livius then; Michieletto Ivan; WO03/040140,2003-3-15] or oxalyl chloride [Doris P.Schumacher, Florham Park; Bruce L.Murphy; Elizabeth, et al., US4; 731; 447,1988-3-15] the preparation acyl chlorides, obtain by Fourier Dare-Kerafyrm thatch reaction; this centre physical efficiency obtains ratio defective product Loratadine [Alberto Stampa with N-Vinyl chloroformate-4-piperidone reaction under the condition of gentleness then; Pelayo Camps, Gloria Rodriguez, et al.; US6; 084,100,2000-7-4].This route has avoided using the super acid of particular device, thereby can reduce the facility investment of production, reduced pollution to environment, but a big shortcoming of this route is that the yield of reaction is low with respect to aforementioned route, as with 3-[2-(3-chloro-phenyl-) ethyl]-the 2-pyridine carbonitrile is a raw material, by hydrolysis, sulfur oxychloride prepares acyl chlorides, and then the yield that carries out the reaction of Fourier Dare-Kerafyrm thatch has only 50%.Total time of reaction is also longer, and this three-step reaction altogether need be near 30 hours, and when preparing with oxalyl chloride, though yield has 50% to bring up to 63%, the reaction times is also longer, needs 40 hours altogether.
For above-mentioned two kinds of methods, synthesize Loratadine with intermediate (1) and need use specific equipment, and can cause serious environmental pollution more, relatively low again but intermediate (2) gets yield, reaction times is very long again, and these all can cause the increase of production cost.Therefore, avoid the application of super acid, synthetic intermediate (2) is a research topic highly significant efficiently.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of Loratadine intermediate.
The technical solution used in the present invention is may further comprise the steps:
1) Vanadium Pentoxide in FLAKES of its mass percent 3%～20% of adding in polyphosphoric acid stirs down at 175～240 ℃, becomes homogeneous phase until system;
2) add 3-[2-(3-chloro-phenyl-) ethyl of polyphosphoric acid mass percent 4%～16%]-the 2-pyridine carbonitrile is in the system of step 1), reacted 5～14 hours down at 175～240 ℃, obtain the intermediate 8-chloro-5 of Loratadine, 6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-ketone;
3) from step 2) the Loratadine intermediate that obtains, with volume ratio be 1: 1: 3 ethyl acetate, normal hexane and sherwood oil mixed solvent carry out recrystallization, obtain purity and be 98～99% product.
The beneficial effect that the present invention has is: a kind of synthetic Loratadine intermediate (2) 8-chloro-5 is provided, 6-dihydro-11H-benzo [5,6] suberyl [1,2-b] method of pyridine-11-ketone, improve yield, shortened the time of reaction, simplified operation, thereby make that utilizing intermediate (2) to synthesize Loratadine becomes practical, avoided by CH in the synthetic Loratadine of intermediate (1)
3SO
3H/BF
3, HE/BF
3Deng the application of reagent, the requirement of the reaction pair equipment of Jiang Diing greatly makes a synthetic method with very high industrial utility value.
The method reaction conversion ratio that provides of the present invention reaches 83.7～93.1%, and product yield reaches 62.9～78.2%, and the purity of product reaches 98～99% behind the process recrystallization.
Embodiment
Below in conjunction with embodiment the present invention is further specified:
Embodiment 1:
Add Vanadium Pentoxide in FLAKES (25g) to the PPA (250g) that is heated to 240 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (30g), and under this temperature, reacted 6.5 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 87.9%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98% product, and yield is 67.4%.
Embodiment 2:
Add Vanadium Pentoxide in FLAKES (37.5g) to the PPA (250g) that is heated to 210 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (15g), and under this temperature, reacted 7 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 89.4%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98.4% product, and yield is 72.5%.
Embodiment 3:
Add Vanadium Pentoxide in FLAKES (17.5g) to the PPA (250g) that is heated to 190 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (25g), and under this temperature, reacted 8 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 93.1%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 99% product, and yield is 78.2%.
Embodiment 4:
Add Vanadium Pentoxide in FLAKES (50g) to the PPA (250g) that is heated to 240 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (20g), and under this temperature, reacted 5 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 83.7%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98.7% product, and yield is 62.9%.
Embodiment 5:
Add Vanadium Pentoxide in FLAKES (7.5g) to the PPA (250g) that is heated to 175 ℃, add 3-[2-(3-chloro-phenyl-) ethyl after stirring into homogeneous phase]-2-pyridine carbonitrile (30g), and under this temperature, reacted 14 hours, the result of reaction is: 3-[2-(3-chloro-phenyl-) ethyl]-transformation efficiency of 2-pyridine carbonitrile reaches 94%, product carries out recrystallization with the mixed solvent of ethyl acetate, normal hexane and sherwood oil (1: 1: 3), and to obtain purity be 98.8% product, and yield is 77.6%.
Claims (1)
1, a kind of synthetic method of Loratadine intermediate is characterized in that may further comprise the steps:
1) Vanadium Pentoxide in FLAKES of its mass percent 3%～20% of adding in polyphosphoric acid stirs down at 175～240 ℃, becomes homogeneous phase until system;
2) add 3-[2-(3-chloro-phenyl-) ethyl of polyphosphoric acid mass percent 4%～16%]-the 2-pyridine carbonitrile is in the system of step 1), reacted 5～14 hours down at 175～240 ℃, obtain the intermediate 8-chloro-5 of Loratadine, 6-dihydro-11H-benzo [5,6] suberyl [1,2-b] pyridine-11-ketone;
3) from step 2) the Loratadine intermediate that obtains, with volume ratio be 1: 1: 3 ethyl acetate, normal hexane and sherwood oil mixed solvent carry out recrystallization, obtain purity and be 98～99% product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510050742 CN1740160A (en) | 2005-07-15 | 2005-07-15 | Synthesis process of loratadine intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510050742 CN1740160A (en) | 2005-07-15 | 2005-07-15 | Synthesis process of loratadine intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1740160A true CN1740160A (en) | 2006-03-01 |
Family
ID=36092708
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510050742 Pending CN1740160A (en) | 2005-07-15 | 2005-07-15 | Synthesis process of loratadine intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1740160A (en) |
-
2005
- 2005-07-15 CN CN 200510050742 patent/CN1740160A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102753532B (en) | Process for preparation of medetomidine | |
| EP1778685B1 (en) | Indolizine carboxamides and the aza and diaza derivatives thereof | |
| CN101805284B (en) | Method for preparing levamlodipine compound | |
| CN102108059A (en) | Method for synthesizing doxylamine succinate | |
| CN106866501A (en) | A kind of preparation method of Levobupivacaine HCL | |
| CN105732484A (en) | Preparation method of Nimodipine | |
| CN106496201A (en) | A kind of preparation method of avanaphil crude drug | |
| CN1740160A (en) | Synthesis process of loratadine intermediate | |
| CN105358529B (en) | A kind of new method of synthesis Eliquis important intermediate | |
| DE60100015T2 (en) | Benzenesulfonamide derivatives and process for their preparation and pharmaceutical compositions containing them | |
| CN101812014B (en) | Amlodipine besylate compound and novel preparation method thereof | |
| CN117756801A (en) | Preparation method of non-neridrone | |
| Nielsen et al. | Assessment of the combined approach of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines using bupivacaine as a model drug | |
| Saubern et al. | Tricyclic-isoxazolidine analogues via intramolecular 1, 3-dipolar cycloaddition reactions of nitrones | |
| NO162421B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PHENYLIN DERIVATIVES AND ACID ADDITION SALTS THEREOF. | |
| CN103641774B (en) | Preparation method of benidipine hydrochloride | |
| CN107573270B (en) | A kind of synthetic method of α-formylpyrrole alkanes compound | |
| CN102174012B (en) | Preparation method of nimodipine | |
| BERGER et al. | PIPERIDINE DERIVATIVES. IV. 4-ALKYL-, 4-CYCLOALKYL-, AND 4-HETEROCYCLYL-PIPERIDINES1 | |
| CN115433123B (en) | Preparation method of loratadine intermediate | |
| CN113943268A (en) | Preparation method of loratadine key intermediate | |
| CN107325055A (en) | A kind of synthetic method of olaparib compound | |
| CN102471326B (en) | Method for producing thiabenzoazulene propionic acid derivative | |
| CN110294708A (en) | The preparation method of trifluoro second seleno phenanthridines and 3,4- dihydro-isoquinoline analog derivative | |
| CN103804265B (en) | The synthesis of a kind of Sulpiride or its optical isomer and post-processing approach |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |