CN102781927A - Process for the preparation of methyl-methyl-3, 4-dihydro-2h-pyran-5-carboxylate - Google Patents
Process for the preparation of methyl-methyl-3, 4-dihydro-2h-pyran-5-carboxylate Download PDFInfo
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- CN102781927A CN102781927A CN2011800111511A CN201180011151A CN102781927A CN 102781927 A CN102781927 A CN 102781927A CN 2011800111511 A CN2011800111511 A CN 2011800111511A CN 201180011151 A CN201180011151 A CN 201180011151A CN 102781927 A CN102781927 A CN 102781927A
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention provides an improved process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV), comprising the steps of: (IV) (i) alkylating 1-Bromo-3-chloropropane of formula (I) with Methylacetoacetate of formula (II) to prepare haloketone of formula (VII) in presence of an alcoholic solvent; (I) (II) (VII) (ii) O-alkylating the compound of formula (VII) with sodium methoxide to obtain the desired molecule methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) in its crude form; (VII) (IV) (iii) Purifying the content of step (ii) above by fractional distillation to obtain the purified molecule of formula (IV).
Description
Technical field
The present invention relates to methyl-methyl-3 of chemical formula (IV); A kind of simple, economical, the preparation technology that do not destroy environment and improved of 4-dihydro-2H-pyrans-5-carboxylicesters, this compound can be used as the midbody in the 6-chlorine hexanone of synthetic main compound chemistry formula V.
Background technology
Methyl-the methyl-3 of chemical formula (IV), 4-dihydro-2H-pyrans-5-carboxylicesters also is called methyl 3,4-dihydro-6-methyl-2H-pyrans-5-carboxylicesters or 2H-pyrans-5 carboxylic acid; 3; 4-dihydro-6-methyl, methyl esters or 5,6-dihydro-3-methoxycarbonyl-2-methyl-4H-pyrans.Many researchs have been carried out in the said compound of preparation field.But, find that such compound can be widely used as the midbody of the 6-chlorine hexanone of synthetic main compound chemistry formula V, and 6-chlorine hexanone is the important component of preparation pharmacy activity component pentoxifylline.
Prior art
United States Patent(USP) No. 3422107 discloses the technology of the said compound of preparation chemical formula (IV), and its denomination of invention is " a kind of oxyalkyl dimethyl xanthine and preparation technology thereof ".Open and a kind of production technique that is characterised in that the compound oxyalkyl dimethyl xanthine of its hypotoxic remarkable vasodilation effect of requirement protection of this prior art.Soluble in water and the lipid of this compound of said explained hereafter.Therefore, said product has application widely in therepic use.
As the equational part of entire reaction in this prior art; The said compound of chemical formula (IV) is as salt of wormwood, 700.0ml ethanol, the 404.0g 1 of midbody compound through mixed reactant 560.0g; 3-dibromopropane and 260.0g methyl aceto acetate, and prepare 60 ℃ of heating.After this habituation, reaction mixture refluxed 5 hours.Normal pressure is the most of ethanol of distillation down.Residue mixes with 1500.0ml water.Separate the oil reservoir that obtains, use the benzene aqueous phase extracted.The benzene layer that obtains is mixed with said oil.After dried over sodium sulfate, benzene is steamed, and the fractionation resistates.Thus, obtain 2-methyl-3-ethoxycarbonyl-5 of 250.0g, the 6-dihydropyrane.
Feasibility in view of above-mentioned prepared chemical formula (IV) compound; And recognize this compound importance as important intermediate in synthetic chemistry formula V compound, will appreciate that certainly that needs satisfy to reduce cost, protect ecology to avoid preparing in the prior art demand of the pollution that causes in chemical formula (IV) the compound technological process.
The shortcoming of prior art
(i) main drawback of prior art invention is and must handles effectively waste water that so that it does not contain all harmful chemicals, this makes its inefficiency;
(ii) produce waste water in a large number, dispose these waste water trouble that becomes very;
(iii) need a large amount of water to take the salt that produces in the solubilizing reaction in the reaction;
(iv) solvent uses the back not reclaim;
(expensive raw materials of v) using and difficult the acquisition;
(vi) carry out these reactions step and become very expensive and consuming time at business level; With
(vii) used the highly carcinogenic and unsafe I level of environment solvent (benzene) to extract the compound of required chemical formula (IV).
The object of the invention
Main purpose of the present invention is that the waste water that design produces reduces preparation methyl-methyl-3 of four times, the method for 4-dihydro-2H-pyrans-5-carboxylicesters.
Another object of the present invention is a kind of preparation methyl-methyl-3 of invention, the method for 4-dihydro-2H-pyrans-5-carboxylicesters, and it has utilized the sodium methylate that needs the salt that considerably less water takes to produce in the solubilizing reaction process.
Another object of the present invention is a kind of method for preparing methyl-methyl-3-dihydro-2H-pyrans-5-carboxylicesters of design, and use therein solvent is recovered and utilizes.
Another object of the present invention is a kind of method for preparing methyl-methyl-3-dihydro-2H-pyrans-5-carboxylicesters that in its reaction process, need not use any solvent of exploitation, and this makes, and this technology is simple, economy and environmental friendliness.
Another object of the present invention is to propose to use easily and the preparing raw material methyl-methyl-3 that is easy to obtain the method for 4-dihydro-2H-pyrans-5-carboxylicesters.
Another object of the present invention is the preparation methyl-methyl-3 that proposes to be applicable to commercial prodn, the method for 4-dihydro-2H-pyrans-5-carboxylicesters.
Advantage of the present invention
According to preparation methyl-methyl-3 of the present invention, the technology of 4-dihydro-2H-pyrans-5-carboxylicesters is carried out under the condition that has sodium methylate rather than salt of wormwood, and sodium methylate has lower molecular weight, needs the water of less amount that it is dissolved.The present invention also proposes to hang down 2.5 times as the molecular weight ratio salt of wormwood of the sodium methylate of reactant, therefore in technological process of the present invention, forms salt still less.The requirement of the sodium methylate of chemical formula (III) is significantly less than the requirement of salt of wormwood, thereby makes this technology more economically.
I. and, in technology of the present invention, in the production of chemical formula (IV), the solvent that produces with end product reclaims through distillation and further in the next batch of technology, utilizes again, thereby makes that this technology is more efficient and practice thrift.
Ii. produce salt still less in the present invention, therefore need these salt of water dissolution still less, lack about four times waste water, make this process environments friendly thereby produce than the technology of using salt of wormwood.The all respects of the technology that the present invention proposes make its novelty, simpler and be easy to operate with commercial size.
Iii. in the present invention, do not need catalyzer to drive reaction and carry out forward, make this reaction become thermopositive reaction because add sodium methylate itself.
Summary of the invention
To achieve these goals, the present invention has improved the methyl-methyl-3 of preparation chemical formula (IV), and the improved technology of 4-dihydro-2H-pyrans-5-carboxylicesters comprises the following steps:
(i) in the presence of alcoholic solvent, with the 1-bromo-3-chloropropane of the methyl acetoacetate alkylation chemistry formula (I) of chemical formula (II), with the halogenated ketone of preparation chemical formula (VII);
(ii) the compound of chemical formula (VII) is carried out the O-alkylation to obtain the desired molecule of crude product form, the methyl-methyl-3 of chemical formula (IV), 4-dihydro-2H-pyrans-5-carboxylicesters with sodium methylate;
(iii) through fractionation purifying above-mentioned steps content (ii), with the molecule of the chemical formula (IV) that obtains purifying.
Embodiment
Through big quantity research, the applicant has announced a kind of initiative technology, and in view of its feature, it is the simple and economic technology of the compound of preparation chemical formula (IV):
A. avoid the use of excessive salt of wormwood;
B. waste water is minimized;
C. use the raw material of desirable and easy acquisition;
D. developed and be suitable for commercial prodn, and feasible technology.
The present invention that the applicant requires to protect is the methyl-methyl-3 of chemical formula (IV), and a kind of improved novel preparation process of 4-dihydro-2H-pyrans-5-carboxylate salt, this compound can be used as the midbody in the 6-chlorine hexanone of synthetic chemistry formula V.
Therefore, we have developed the improvement technology of the compound of preparation chemical formula (IV), and it is schematic illustration in following equation-I:
Equation-I
Here, 1-bromo-3-chloropropane is the critical materials that carries out this condensation reaction.Methyl acetoacetate is as the activity methene compound of this condensation reaction.Sodium methylate is also as reactant.
The reactions step that relates among the present invention can be summarized as follows:
(1) must side chain preparation begin from the halogenated ketone of the methyl acetoacetate condensation prepared chemical formula (VII) of 1-bromo-3 chloropropanes of chemical formula (I) and chemical formula (II).
(2) under variable reaction conditions, the halogenated ketone of chemical formula (VII) is carried out the O-alkylation with sodium methylate, producing the desired molecule of crude product form, the methyl-methyl-3 of chemical formula (IV), 4-dihydro-2H-pyrans-5-carboxylicesters produces methyl alcohol simultaneously.
(3) methyl-methyl-3 of fractionation purifying crude product molecular chemistry formula (IV) then, 4-dihydro-2H-pyrans-5-carboxylicesters.
Improve in the technology at this, this is reflected under the alcoholic solvent existence and carries out, and said alcoholic solvent is selected from the group of being made up of methyl alcohol, ethanol, Virahol or n-propyl alcohol, amylalcohol, hexanol and propyl alcohol, particular methanol.This improvement technology can be carried out with the sodium methylate of solution and powder type, and said solution suitably is selected from the Fatty Alcohol(C12-C14 and C12-C18) of C1 to C6 carbon atom, particular methanol.In the condensation course of chemical formula (I) compound and chemical formula (II) compound, and in the cyclization process of the halogenated ketone of the following chemical formula (VII) of the sodium methylate of chemical formula (III) existence, methyl alcohol also generates with stoichiometric ratio.The methyl alcohol initial amount that the methyl alcohol of this growing amount uses when beginning together with reaction reclaims.Recovery methyl alcohol in the last generation of each batch is distilled and is utilized in the next batch, therefore the back batch in need not add methyl alcohol.This makes and should reaction practice thrift very much and environmental friendliness.
In this technology, temperature of reaction remains in 0 ℃ to the 95 ℃ scope.Than the salt of wormwood (K that uses in the prior art
2CO
3) sodium methylate of low 2.5 times of molecular weight is used for the present invention.Therefore the salt that forms also still less causes the water demand of these salt of needs dissolving to reduce.Therefore, also reduced the amount of the sewage that produces.The present invention does not need always under nitrogen atmosphere, to carry out, during except adding sodium methylate in reactor drum.It can also be seen that because add heat release condition that sodium methylate should reaction in reactant the time in the reaction process, this is reflected under the condition that does not have catalyzer and carries out.The present invention comes the compound of extraction chemistry formula (IV) without any need for solvent, and this makes, and this technology is simple, economy and environmental friendliness.
The mode of only describing the present invention's " improvement technology of the compound of a kind of preparation chemical formula (IV) " in detail and carrying out through operation embodiment hereinafter with the mode of explanation.Therefore, these embodiment should not think to limit the scope of the present invention to the described scope of hereinafter.
Embodiment-1
At 30-40 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 250.0g (2.15mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add 160.0g (2.96mol) sodium methylate of powder type lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55-60 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 250.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
Embodiment-2
At 30-40 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 250.0g (2.15mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add 184.0g (3.4mol) sodium methylate of powder type lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55-60 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 205.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
Embodiment-3
At 30 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 250.0g (2.15mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add 208.0g (3.84mol) sodium methylate of powder type lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 196.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
Embodiment-4
At 30 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 250.0g (2.15mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add 240.0g (4.44mol) sodium methylate of powder type lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 188.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
Embodiment-5
At 30 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 250.0g (2.15mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add 280.0g (5.18mol) sodium methylate of powder type lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 164.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
Embodiment-6
At 30 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 250.0g (2.15mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add the sodium methylate (2.96mol) that is dissolved in alcoholic solvent (for example methyl alcohol) of 800.0g20% lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 248.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
Embodiment-7
At 30 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 250.0g (2.15mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add the sodium methylate (2.96mol) that is dissolved in alcoholic solvent (for example methyl alcohol) of 640.0g25% lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 247.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
Embodiment-8
At 30-40 ℃, do not keep under the condition of nitrogen atmosphere, in 780.0ml alcoholic solvent (particular methanol), add 315.0g (2.0mol) 1-bromo-3-chloropropane and 290.0g (2.5mol) methyl acetoacetate.At 30-40 ℃, under the condition of nitrogen atmosphere, in above-mentioned content, add 160.0g (2.96ml) sodium methylate of powder type lentamente in batches.Because this exothermic heat of reaction must keep nitrogen atmosphere, the temperature of RM raises immediately.Under the reflux temperature of 70 ℃ (boundaries), keep and to react 10-12 hour, preferred 6-8 hour, RM is cooled to 55 ℃.Under atmospheric pressure add about 315.0g water in this stage, all salt that will form when will react is all soluble in water.The solvent methanol that uses the compound that obtains unreacted chemical formula (I) from the fractionation of crude product and the reaction.Through fractionation recovered solvent methyl alcohol is not respective pure form, and its purity is less than 90%.Therefore, before this solvent of recycling, obtain the solvent of respective pure form (NLT90% purity) once more through fractionation, to be used for the reaction of next batch.At last, obtain the compound of the pure chemical formula of 238.0g (IV).The end product that obtains in the technology of the present invention is for liquid, and specific density is 1.1.
We want through changing the amount and the solvent of reactant, with tabulated form to the above-mentioned experiment generalized data form that draws, as the instrument of the process parameter optimizing of the compound of plant-scale scale operation chemical formula (IV).
In all experiments of from embodiment 1-8, carrying out, through changing reaction parameter, we observe, and amount/loadings (shown in embodiment 1 to 6) of comparing the rising sodium methylate with other reactants has negative impact (that is reduction) to the yield of end product.In embodiment 8, observe and also observe identical trend for the reactant methyl acetoacetate.Equally, see in embodiment 6 and 7 that extra solvent (in the alcoholic solution process that adds sodium methylate) does not influence the yield of end product.In embodiment 1,6 and 7, obtain the optimal yield of final pure products.In our extensive/commercial prodn industry, can adhere to using embodiment 1,6 and 7, the reactant ratio of most preferred embodiment 1.
We find with tabulated form drawn technology and the comparative result of the present invention of prior art invention US3422107 that these two kinds of technologies have significant difference.
Comparison sheet
From this comparison sheet, we confirm that the present invention has improvement and more efficient in many aspects than prior art processes.Prior art processes needs the strong waste water of handling so that it does not contain harmful chemical substance, and this makes that this process efficiency is low.Waste water produces in a large number, if this technology is carried out with commercial size, handles these waste water trouble that will become very so.Need a large amount of water to take the salt that forms in the solubilizing reaction process in the reaction process, and do not reclaim solvent after using.Require the present invention of protection to extract purpose compound/product without any need for additional solvent, this makes, and this technology is simple, economy and environmental friendliness.And in the prior art, the alcoholic solvent that uses in the reaction is not mentioned yet and will be utilized again.On the contrary, the compound owing to chemical formula (III) among the present invention is that sodium methylate has generated solvent, thereby has reduced solvent consumption, therefore makes this technology provide cost savings.Invention disclosed herein has no shortcoming, and very friendly to environment.
Claims (11)
1. methyl-methyl-3 for preparing chemical formula (IV), the improved method of 4-dihydro-2H-pyrans-5-carboxylicesters comprises the following steps:
(i) in the presence of alcoholic solvent, with the 1-bromo-3-chloropropane of the methyl acetoacetate alkylation chemistry formula (I) of chemical formula (II), with the halogenated ketone of preparation chemical formula (VII);
(ii) the compound of chemical formula (VII) is carried out the O-alkylation to obtain the desired molecule of crude product form, the methyl-methyl-3 of chemical formula (IV), 4-dihydro-2H-pyrans-5-carboxylicesters with sodium methylate;
(iii) through fractionation purifying above-mentioned steps content (ii), with the molecule of the chemical formula (IV) that obtains purifying.
2. the method for claim 1, wherein said alcoholic solvent is selected from the group of being made up of methyl alcohol, ethanol, Virahol or n-propyl alcohol.
3. according to claim 1 or claim 2 method, wherein said alcoholic solvent most preferably is methyl alcohol.
4. each described method as in the above-mentioned claim, wherein sodium methylate is used with dry powder or solution form in (ii) in the step of claim 1, and said solution suitably is selected from has C
1To C
6The Fatty Alcohol(C12-C14 and C12-C18) of carbon atom.
5. the method for claim 1, the molar ratio of wherein said reactant 1-bromo-3-chloropropane, methyl acetoacetate and sodium methylate remains on 1: 1.07: 1.48 to 1: 1.25: 2.59 ratio.
6. like the described method of aforementioned each claim, wherein the (ii) middle sodium methylate that adds of the step of claim 1 is preferably used with powder type.
7. the method for claim 1 wherein only keeps nitrogen atmosphere in adding the sodium methylate process.
8. the method for claim 1, said method comprises the fractionation of crude product, wherein said solvent by generate once more with the back batch in utilize again.
9. the method for claim 1; Wherein said solvent is in the condensation and the cyclisation of the compound of the compound of chemical formula (I) and chemical formula (II); And produce with stoichiometric ratio in the cyclization process of the halogenated ketone of chemical formula (VII); Methyl alcohol with initial amount reclaims, and distillation also utilizes in follow-up batch again.
10. the method for claim 1, the temperature of wherein reacting described in each step remains between 0 ℃ to 95 ℃.
11. the method for claim 1, the said end product that wherein obtains after the fractionation are liquid, have 1.1 specific density.
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| IN544/MUM/2010 | 2010-03-02 | ||
| IN544MU2010 | 2010-03-02 | ||
| PCT/IN2011/000111 WO2011108001A2 (en) | 2010-03-02 | 2011-02-24 | Process for the preparation of methyl-methyl-3, 4-dihydro-2h-pyran-5-carboxylate |
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| WO2023228083A1 (en) * | 2022-05-23 | 2023-11-30 | Ami Organics Ltd. | A process for the preparation of pentoxifylline intermediate |
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| CN116178136B (en) * | 2023-04-28 | 2023-07-14 | 北京天弘天达科技股份有限公司 | Preparation method of 2-hexyl decanoic acid |
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| US3422107A (en) * | 1964-09-05 | 1969-01-14 | Albert Ag Chem Werke | Certain oxoalkyldimethylxanthines and a process for the preparation thereof |
| DD226709A1 (en) * | 1984-09-03 | 1985-08-28 | Robotron Elektronik | MULTIPLEXERS FOR LOW-CHANNEL DIGITAL TRANSMISSION SYSTEMS |
| CN1439637A (en) * | 2002-02-21 | 2003-09-03 | 拜尔公司 | Preparation of 3,6-dihydro-2H-pyrane-2-carboxylic ester |
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| DD266709A3 (en) * | 1984-09-05 | 1989-04-12 | Dresden Arzneimittel | PROCESS FOR PREPARING 2-METHYL-5,6-DIHYDRO-PYRAN-3-CARBOXYLIC ACID ESTERS |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023228083A1 (en) * | 2022-05-23 | 2023-11-30 | Ami Organics Ltd. | A process for the preparation of pentoxifylline intermediate |
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| Publication number | Publication date |
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| WO2011108001A2 (en) | 2011-09-09 |
| WO2011108001A3 (en) | 2011-11-10 |
| CN102781927B (en) | 2016-02-03 |
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