CN105906531A - Preparation method of pimavanserin intermediate - Google Patents
Preparation method of pimavanserin intermediate Download PDFInfo
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- CN105906531A CN105906531A CN201510979027.4A CN201510979027A CN105906531A CN 105906531 A CN105906531 A CN 105906531A CN 201510979027 A CN201510979027 A CN 201510979027A CN 105906531 A CN105906531 A CN 105906531A
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- China
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- preparation
- isobutoxy
- isocyanatometyl
- benzene
- dichloromethane
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- VLLWPXUBAFBGCN-UHFFFAOYSA-N CC(C)(COCC(OC(N)(N)N)=O)N Chemical compound CC(C)(COCC(OC(N)(N)N)=O)N VLLWPXUBAFBGCN-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a pimavanserin intermediate which is 1-isobutoxy-4-isocyanatomethylbenzene. The preparation method comprises that 4-isobutoxyphenylmethanamine as an initial raw material and a bis(trichloromethyl)carbonate solution undergo a reaction under appropriate conditions to produce a desired product. The preparation method is free of highly toxic chemicals, has stable processes and a high yield and is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly to the preparation method of a kind of Mo Fanselin intermediate.
Background technology
Compound of formula I N-(4-luorobenzyl)-N-(1-methyl piperidine-4-base)-N'-(4-(2-isobutoxy) benzyl) urea, common name Mo Fanselin (Pimavanserin), it it is the specific inverse agonist of a kind of serotonin 2A hypotype, it reaches 40 times relative to the selectivity of serotonin 2C subtype acceptor, activity is not then had for serotonin 2B subtype acceptor and dopamine receptor, therefore does not affect the normal effect of dopamine.Mo Fanselin is researched and developed (trade name: Nuplazid) by drugmaker of Acadia of the U.S. (Acadia Pharmaceuticals), treatment for parkinsonism related psychiatric conditions, currently carry out III clinical trial phase, authorized breakthrough medicine status by U.S. FDA in September, 2014.
Compound PCT Patent Application WO0166521 of Mo Fanselin is proposed in calendar year 2001 by Acadia's pharmacy, and the synthetic route of the open report of this compound is loaded in this race's patent at present.According to U.S. patent documents US6815458, this synthetic route is:
In above-mentioned route, intermediate III, i.e. the preparation process of 1-isobutoxy-4-isocyanatometyl benzene has used phosgene.Phosgene is the severe poisonous chemicals that a kind of boiling point is relatively low, huge to personnel health and ambient influnence and strictly regulated, and needs special corollary equipment, has inconvenience for industrialized production.
Summary of the invention
The present invention seeks to seek to set up one and do not use that severe poisonous chemicals, yield are higher, cost is relatively low, the 1-isobutoxy-4-isocyanatometyl benzene of production suitable for industrialized, i.e. a Mo Fanselin intermediate III synthetic route.
Technical scheme is as follows:
Step 1: with the 4-i.e. compound IV of isobutoxy phenyl methylamine as initiation material, compound IV is dissolved in organic solvent A, it is added thereto to the solution A of double (trichloromethyl) carbonic ester again, wherein said organic solvent A is selected from chloroform, dichloromethane, acetone, oxolane, more preferably dichloromethane；
Step 2: above-mentioned reaction system stirs reaction right times at appropriate temperatures, and wherein temperature is-15～20 DEG C, more preferably-5～5 DEG C；
Step 3: obtaining compound III after above-mentioned reaction system properly being post-processed, wherein post processing mode is extraction and washing, more preferably uses dichloromethane to extract, and use saturated sodium bicarbonate solution washs.
The reaction scheme of described preparation method is as follows:
The creativeness of the present invention is:
1, in synthetic route disclosed by the invention, 4-isobutoxy phenyl methylamine obtains target compound 1-isobutoxy-4-isocyanatometyl benzene with double (trichloromethyl) carbonate reactions, whole course of reaction gentleness is controlled, post-processing simple and easy to do, process does not use and does not the most produce severe poisonous chemicals.
2, synthetic route process stabilizing disclosed by the invention, target product reliable in quality, production cost is reasonable, is suitable for industrial production.
Detailed description of the invention
Illustrate the present invention below with reference to embodiment, but present disclosure is not limited to specific embodiment, all parts belonging to the present invention based on technology of the present invention.
In the present invention, room temperature is defaulted as 25 DEG C.
In the present invention, the stirring clearly not limited rotating speed is convention stir mode, and rotating speed is 100～300 rpms.
The present invention is raw materials used is commercially available technical grade product.
Embodiment 1:
Step 1: under room temperature, adds 840mL dichloromethane and 90g compound IV in there-necked flask, stirs and uses cryosel bath be cooled to-5～0 DEG C of intervals and keep stable after being completely dissolved.Dropping mode is used to be added in reactant liquor with the speed of 20mL/min by double for the 0.625mol/L of 160mL (trichloromethyl) carbonic ester dichloromethane solutions.
Step 2: after the dropping of double (trichloromethyl) carbonate solution is complete, keeps cryosel to bathe in-5～0 DEG C of intervals, continues stirring reaction 2h, is to slowly warm up to room temperature afterwards in 1h, at room temperature continues stirring reaction 3h.
Step 3: stir 30min after adding 2000mL purified water in reaction system, removed by aqueous phase after layering, uses 500mL dichloromethane to be extracted twice, then the organic phase after extraction is merged with the organic phase of former reaction system.Organic phase after merging successively uses the saturated nacl aqueous solution of the 1mol/L hydrochloric acid solution of 500mL, the saturated sodium bicarbonate solution of 500mL and 500mL to wash, after washing, solution is dried with the dried air blast of anhydrous sodium sulfate, obtain pale solid 17.9g, i.e. target compound 1-isobutoxy-4-isocyanatometyl benzene, productivity 87%.
Claims (4)
1. a preparation method for 1-isobutoxy-4-isocyanatometyl benzene, comprises the following steps:
1) with 4-isobutoxy phenyl methylamine as initiation material, initiation material is dissolved in organic solvent A, then
Add the solution A of double (trichloromethyl) carbonic ester；
2) stir at appropriate temperatures above-mentioned reaction system certain time；
3) above-mentioned reaction system is properly post-processed to obtain target compound.
The preparation method of 1-isobutoxy-4-isocyanatometyl benzene the most according to claim 1, it is characterised in that
Described organic solvent A is selected from chloroform, dichloromethane, acetone, oxolane, more preferably dichloromethane.
The preparation method of 1-isobutoxy-4-isocyanatometyl benzene the most according to claim 1, it is characterised in that
Described suitable temperature is-15～20 DEG C, more preferably-5～5 DEG C.
The preparation method of 1-isobutoxy-4-isocyanatometyl benzene the most according to claim 1, it is characterised in that
Described post processing is extraction and washing, more preferably uses dichloromethane to extract, uses saturated sodium bicarbonate molten
Liquid washs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510979027.4A CN105906531A (en) | 2015-12-23 | 2015-12-23 | Preparation method of pimavanserin intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510979027.4A CN105906531A (en) | 2015-12-23 | 2015-12-23 | Preparation method of pimavanserin intermediate |
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| CN105906531A true CN105906531A (en) | 2016-08-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510979027.4A Pending CN105906531A (en) | 2015-12-23 | 2015-12-23 | Preparation method of pimavanserin intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107118209A (en) * | 2016-02-25 | 2017-09-01 | 西华大学 | Pyrido [3,4-b ] indolylurea compounds and application thereof as IDO (intermediate compound) inhibitor |
| CN108794351A (en) * | 2018-07-26 | 2018-11-13 | 丽珠集团新北江制药股份有限公司 | A kind of preparation method of Mo Fanselin key intermediate |
| CN108947891A (en) * | 2018-07-26 | 2018-12-07 | 丽珠集团新北江制药股份有限公司 | The method for safely preparing a Mo Fanselin and its tartrate using triphosgene |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443167A (en) * | 2000-03-06 | 2003-09-17 | 阿卡蒂亚药品公司 | Azacyclic compounds for use in treatment of 5-serotonin related diseases |
-
2015
- 2015-12-23 CN CN201510979027.4A patent/CN105906531A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443167A (en) * | 2000-03-06 | 2003-09-17 | 阿卡蒂亚药品公司 | Azacyclic compounds for use in treatment of 5-serotonin related diseases |
Non-Patent Citations (2)
| Title |
|---|
| DAZHI LIU，ET AL: "Design, synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| VALDEMAR L. ANDERSEN，ET AL: "11C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107118209A (en) * | 2016-02-25 | 2017-09-01 | 西华大学 | Pyrido [3,4-b ] indolylurea compounds and application thereof as IDO (intermediate compound) inhibitor |
| CN107118209B (en) * | 2016-02-25 | 2019-06-25 | 西华大学 | Pyrido [3,4-b ] indolylurea compounds and application thereof as IDO (intermediate compound) inhibitor |
| CN108794351A (en) * | 2018-07-26 | 2018-11-13 | 丽珠集团新北江制药股份有限公司 | A kind of preparation method of Mo Fanselin key intermediate |
| CN108947891A (en) * | 2018-07-26 | 2018-12-07 | 丽珠集团新北江制药股份有限公司 | The method for safely preparing a Mo Fanselin and its tartrate using triphosgene |
| CN108794351B (en) * | 2018-07-26 | 2021-02-09 | 丽珠集团新北江制药股份有限公司 | Preparation method of pimavanserin key intermediate |
| US10934257B2 (en) | 2018-07-26 | 2021-03-02 | Livzon New North River Pharmaceutical Co., Ltd. | Method for preparing pimavanserin and tartrate thereof by using triphosgene |
| EP3828170A4 (en) * | 2018-07-26 | 2021-12-15 | Livzon New North River Pharmaceutical Co., Ltd. | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene |
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Application publication date: 20160831 |
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