CN107759634A - A kind of Wittig tube- nurseries method - Google Patents
A kind of Wittig tube- nurseries method Download PDFInfo
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- CN107759634A CN107759634A CN201711048513.XA CN201711048513A CN107759634A CN 107759634 A CN107759634 A CN 107759634A CN 201711048513 A CN201711048513 A CN 201711048513A CN 107759634 A CN107759634 A CN 107759634A
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- wittig
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- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of Wittig tube- nurseries method,（1）α halogen esters and triaryl phosphine are raw material, are reacted in two-phase solvent under the conditions of halo metal salt catalyst, and reaction terminates rear split-phase, organic phase recovery, and aqueous crystallization obtains quaternary alkylphosphonium salt, and disposing mother liquor is applied mechanically；（2）Step（1）In obtain quaternary alkylphosphonium salts and reacted in aqueous phase under the conditions of base reagent, after reaction terminates, crystallisation by cooling obtains product.Whole course of reaction mild condition of the invention, and it is easy to operate, high income, cost are low, and quantity of three wastes is few, are adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of Wittig tube- nurseries method.
Background technology
Wittig reagents are a kind of organic reagents of extensive application value, in multi-medicament intermediate and natural products
It is fully synthetic in have the applications of Wittig reagents, such as ethoxycarbonyl ethylidene triphenylphosphine, be both Novartis's cardiovascular drug
Thing AHU-377 intermediate, and the anti-hepatitis medicine Suo Feibuwei intermediates of Gilead.
The conventional preparation method of Wittig reagents is triphenylphosphine and organohalogen compounds in organic solvent (such as toluene, acetic acid
Ethyl ester, tetrahydrofuran etc.) in effect generation quaternary alkylphosphonium salt, then aprotic solvent (such as tetrahydrofuran, DMF,
Dimethyl sulfoxide, ether etc.) in plus alkali (such as n-BuLi, Sodamide, sodium alkoxide, potassium hydroxide, triethylamine) processing, lose portion
Sub- hydrogen halides forms.
It is unstable to air and water because Wittig reagents are very active, therefore typically made under the conditions of anhydrous and oxygen-free
It is standby, and do not separated typically in synthesis, directly carry out the reaction with aldehyde, ketone in next step.
The content of the invention
It is an object of the invention to provide a kind of mild condition, Wittig tube- nurseries method easy to operate.
The present invention technical solution be：
A kind of Wittig tube- nurseries method, it is characterized in that：Including following operating procedure：
(1) alpha-halogen -ester and triaryl phosphine are raw material, are carried out in two-phase solvent under the conditions of halo metal salt catalyst anti-
Should, reaction terminates rear split-phase, organic phase recovery, and aqueous crystallization obtains quaternary alkylphosphonium salt, and disposing mother liquor is applied mechanically；
(2) quaternary alkylphosphonium salts are obtained in step (1) to be reacted in aqueous phase under the conditions of base reagent, after reaction terminates, cooling
Crystallization obtains product；
Reaction equation：
Described in step (1) in alpha-halogen -ester halogen X be chlorine, bromine or iodine, substituent R1For hydrogen atom, alkyl, alkenyl or
Aryl, substituent R2For hydrogen atom, alkyl, alkenyl or aryl；Substituent R is aryl or substituted aryl in triaryl phosphine reagent；
Halogen X is chlorine, bromine or iodine in halo metal salt, and metal M is alkali metal；Reaction dissolvent is organic solvent and water two-phase system；Have
Solvent is esters, alkyl halide hydro carbons, aromatic hydrocarbons, ethers or alkanes water-insoluble solvent.
Alpha-halogen -ester described in step (1) is 1 with triaryl phosphine mol ratio:0.5-1:2；Alpha-halogen -ester and halo metal
Salt catalyst mol ratio is 1:0.01-1:0.5.
Base reagent inorganic base or organic base described in step (2)；Reaction dissolvent is water.
The inorganic base is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, caustic alcohol or sodium tert-butoxide；It is described organic
Alkali is triethylamine or pyridine.
Quaternary alkylphosphonium salt described in step (2) is 1 with base reagent mol ratio:0.9-1:3.
The present inventor is found through experiments that this kind of Wittig prepared for alpha-halogen -ester and triaryl phosphine is tried
Agent, because its stability is preferable, therefore it can be reacted in the presence of water, also, the addition of water, not only contribute to season
The purifying of phosphonium salt, also the recovery beneficial to solvent in quaternary alkylphosphonium salt preparation process and apply mechanically.Finally, the optimization to technique, this hair are passed through
Bright whole course of reaction mild condition, and it is easy to operate, high income, cost are low, and quantity of three wastes is few, are adapted to industrialized production.
With reference to embodiment, the invention will be further described.
Embodiment
Embodiment 1：
The preparation of ethoxycarbonyl methylene triphenyl phosphine
(1) preparation of carbethoxymethyl triphenyl phosphine dichloride：
At 0-10 DEG C, the aqueous solution of sodium iodide (12g) is added into triphenylphosphine (88g) dichloromethane solution, then
Alpha-chloro-ethyl acetate (41g) is added, reacts 30h at 40-45 DEG C；After reaction completely, split-phase, aqueous phase cooling, crystallization, mistake
Filter obtains carbethoxymethyl triphenyl phosphine dichloride (125g)；Organic phase recovery, aqueous phase disposing mother liquor are applied mechanically.
(2) preparation of ethoxycarbonyl methylene triphenyl phosphine：
Carbethoxymethyl triphenyl phosphine dichloride (125g) is added in water at 0-10 DEG C, inflated with nitrogen, is heated to 60-70
DEG C, potassium hydroxide (20g) aqueous solution is added, is incubated 5h；Reaction solution cooling, filter, filter cake is washed with water, and is dried to obtain methylamino ethoxy
Acylmethylene triphenylphosphine (105g).
Embodiment 2：
The preparation of ethoxycarbonyl methylene triphenyl phosphine (solvent is applied mechanically)
(1) preparation of carbethoxymethyl triphenyl phosphine dichloride (solvent is applied mechanically)：
At 0-10 DEG C, into triphenylphosphine (88g) dichloromethane solution, (first step of embodiment 1 reclaims organic phase) adds
The aqueous solution (first step of embodiment 1 reclaims crystalline mother solution) of sodium iodide (3g), then adds alpha-chloro-ethyl acetate (41g),
30h is reacted at 40-45 DEG C；After reaction completely, split-phase, aqueous phase cooling, crystallization, carbethoxymethyl triphenyl chlorine is filtrated to get
Change phosphine (127g)；Organic phase recovery, aqueous phase mother liquid recycle.
(2) preparation of ethoxycarbonyl methylene triphenyl phosphine：
Carbethoxymethyl triphenyl phosphine dichloride (127g) is added in water at 0-10 DEG C, inflated with nitrogen, is heated to 60-70
DEG C, potassium hydroxide (20g) aqueous solution is added, is incubated 5h；Reaction solution cooling, filter, filter cake is washed with water, and is dried to obtain methylamino ethoxy
Acylmethylene triphenylphosphine (108g).
Embodiment 3：
The preparation of ethoxycarbonyl ethylidene triphenylphosphine
(1) preparation of ethoxycarbonyl ethyltriphenylphosphonium bromide：
At 20-30 DEG C, the aqueous solution of KI (6g) is added into triphenylphosphine (88g) toluene solution, is then added
Alpha-brominated-ethyl propionate (60g), reacts 15h at 70-75 DEG C；After reaction completely, split-phase, aqueous phase cooling, crystallization, filter
To ethoxycarbonyl ethyltriphenylphosphonium bromide (142g)；Organic phase recovery, aqueous phase disposing mother liquor are applied mechanically.
(2) preparation of ethoxycarbonyl ethylidene triphenylphosphine：
Ethoxycarbonyl ethyltriphenylphosphonium bromide (142g) is added in water at 20-30 DEG C, inflated with nitrogen, is heated to 40-
50 DEG C, sodium hydroxide (27g) aqueous solution is added, is incubated 6h；Reaction solution cooling, filter, filter cake is washed with water, and is dried to obtain ethoxy
Formoxyl ethylidene triphenylphosphine (110g).
Embodiment 4：
The preparation of ethoxycarbonyl ethylidene triphenylphosphine (solvent is applied mechanically)
(1) preparation of ethoxycarbonyl ethyltriphenylphosphonium bromide：
At 20-30 DEG C, iodine is added into triphenylphosphine (88g) toluene solution (first step of embodiment 3 reclaims organic phase)
Change the aqueous solution (first step of embodiment 3 reclaims mother liquor) of potassium (3g), alpha-brominated-ethyl propionate (60g) is then added, in 70-75
15h is reacted at DEG C；After reaction completely, split-phase, aqueous phase cooling, crystallization, ethoxycarbonyl ethyltriphenylphosphonium bromide is filtrated to get
(144g)；Organic phase recovery, aqueous phase disposing mother liquor are applied mechanically.
(2) preparation of ethoxycarbonyl ethylidene triphenylphosphine：
Ethoxycarbonyl ethyltriphenylphosphonium bromide (144g) is added in water at 20-30 DEG C, inflated with nitrogen, is heated to 40-
50 DEG C, sodium hydroxide (27g) aqueous solution is added, is incubated 6h；Reaction solution cooling, filter, filter cake is washed with water, and is dried to obtain ethoxy
Formoxyl ethylidene triphenylphosphine (112g).
Claims (6)
1. a kind of Wittig tube- nurseries method, it is characterized in that：Including following operating procedure：
(1) alpha-halogen -ester and triaryl phosphine are raw material, are reacted in two-phase solvent under the conditions of halo metal salt catalyst,
Reaction terminates rear split-phase, organic phase recovery, and aqueous crystallization obtains quaternary alkylphosphonium salt, and disposing mother liquor is applied mechanically；
(2) quaternary alkylphosphonium salts are obtained in step (1) to be reacted in aqueous phase under the conditions of base reagent, after reaction terminates, crystallisation by cooling
Obtain product；
Reaction equation：
2. Wittig tube- nurseries method according to claim 1, it is characterized in that：Described in step (1) in alpha-halogen -ester
Halogen X is chlorine, bromine or iodine, substituent R1For hydrogen atom, alkyl, alkenyl or aryl, substituent R2For hydrogen atom, alkyl, alkenyl or
Aryl；Substituent R is aryl or substituted aryl in triaryl phosphine reagent；In halo metal salt halogen X be chlorine, bromine or iodine, metal M
For alkali metal；Reaction dissolvent is organic solvent and water two-phase system；Organic solvent is esters, alkyl halide hydro carbons, aromatic hydrocarbons, ethers
Or alkanes water-insoluble solvent.
3. Wittig tube- nurseries method according to claim 1, it is characterized in that：Alpha-halogen -ester described in step (1) with
Triaryl phosphine mol ratio is 1:0.5-1:2；Alpha-halogen -ester is 1 with halo metal salt catalyst mol ratio:0.01-1:0.5.
4. Wittig tube- nurseries method according to claim 1, it is characterized in that：Base reagent is inorganic described in step (2)
Alkali or organic base；Reaction dissolvent is water.
5. Wittig tube- nurseries method according to claim 4, it is characterized in that：The inorganic base is sodium carbonate, carbonic acid
Potassium, sodium hydroxide, potassium hydroxide, caustic alcohol or sodium tert-butoxide；The organic base is triethylamine or pyridine.
6. Wittig tube- nurseries method according to claim 4, it is characterized in that：Quaternary alkylphosphonium salt and alkali described in step (2)
Reagent mol ratio is 1:0.9-1:3.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711048513.XA CN107759634A (en) | 2017-10-31 | 2017-10-31 | A kind of Wittig tube- nurseries method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124570A (en) * | 2022-08-11 | 2022-09-30 | 万华化学集团股份有限公司 | Preparation method of C3 phosphonium salt |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106336357A (en) * | 2016-08-29 | 2017-01-18 | 启东东岳药业有限公司 | Preparation method of 2-hydroxymethyl methyl acrylate |
-
2017
- 2017-10-31 CN CN201711048513.XA patent/CN107759634A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106336357A (en) * | 2016-08-29 | 2017-01-18 | 启东东岳药业有限公司 | Preparation method of 2-hydroxymethyl methyl acrylate |
Non-Patent Citations (1)
| Title |
|---|
| DAVID W. MANLEY ET AL.: ""Titania-Promoted Carboxylic Acid Alkylations of Alkenes and Cascade Addition−Cyclizations"", 《J. ORG. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115124570A (en) * | 2022-08-11 | 2022-09-30 | 万华化学集团股份有限公司 | Preparation method of C3 phosphonium salt |
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