CN107602376A - The synthetic method of Neil before one koji arranges - Google Patents
The synthetic method of Neil before one koji arranges Download PDFInfo
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- CN107602376A CN107602376A CN201711041330.5A CN201711041330A CN107602376A CN 107602376 A CN107602376 A CN 107602376A CN 201711041330 A CN201711041330 A CN 201711041330A CN 107602376 A CN107602376 A CN 107602376A
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Abstract
The invention discloses a kind of your synthetic method of treprostinil, key step includes：It is oxidation of aldehydes to connect acetal, acetal hydro and hydration.The present invention is on the basis of existing technology, explored by many experiments, optimizing raw material matches so that reaction condition is more gentle, shortens the reaction time, improve the yield of product, for high income up to 68%, present invention process is simple, and industrialization large-scale production can be achieved, it can be that enterprise brings good economic benefit, possess wide prospect.
Description
Technical field
The present invention relates to the field of chemical synthesis, relates generally to the synthetic method that a koji arranges preceding Neil.
Background technology
Pulmonary hypertension (Pulmonary hypertension, PH) is the quiescent condition bottom right heart as caused by a variety of causes
The mean pulmonary arterial pressure that conduit measures is more than or equal to 25mmHg one group of clinical pathology physiology syndrome, with the blood of lung parteriole
Pipe spasm, endometrial hyperplasia, middle level plumpness, the formation of outer membrane hyperplasia, primary thrombus, different degrees of inflammation and plexi change etc. are spy
Sign, clinical manifestation are that pulmonary arterial pressure progressive raises and ultimately results in right heart failure.Very poor as a kind of prognosis is clinical common
Angiocardiopathy, for pulmonary hypertension by the vasopasm of lung parteriole, endometrial hyperplasia and reconstruct cause pulmonary vascular resistance to increase
Add, can finally cause right heart failure, in addition it is dead.
Your parenteral solution of treprostinil is one of effective ejection preparation for the treatment of pulmonary hypertension, and overseas clinical trial data show
Show that the clinical drug is curative for effect, security is better than other prostacyclin analogs class medicines listed, stability is preferable, and half
Decline phase length, is mainly administered using subcutaneous continuous infusion mode, also sustainable intravenous infusion administration, transdermal delivery mechanisms are comparatively
Safety, the risk of severe infections septicemia can be reduced.You have good stability to treprostinil, and half-life period in the circulating cycle reaches
To 4 hours；And medicine will not also decompose when passing through lung.Treprostinil that has good bioactivity simultaneously,
Pulmonary hypertension is treated, peripheral artery disease, ischemic lesions, treating improves renal function, nerve foot ulcers, asthma, very
There is the effect of fine to treating cancer aspect.New drug Remodulin using the sodium salt of treprostinil that as main component exists
Obtain within 2004 U.S. Food drug administration (FDA) approval listing.
Due to treprostinil, your molecule is with condensed cyclic structure and more multiple with multiple chiral centers, its building-up process
It is miscellaneous.Aristoff et al. reports synthetic method (the Tetrahedron Lett.1982,23,2067- of treprostinil that first
2070), its synthesis strategy is synthesizing five-membered ring first, then passes through Isosorbide-5-Nitrae-addition reaction and introduces aromatic rings, final reaction cyclization
Hexatomic ring is formed, so as to the final main skeleton for successfully synthesizing treprostinil that.This chiral synthetic route needs 36 steps to react altogether,
It is excessively tediously long, it is unfavorable for synthesizing on a large scale.
Your synthesis of treprostinil is typically using 3- hydroxyls -2- pi-allyls-phenmethylol of phenolic hydroxyl group protection as raw material, through multistep
Reaction obtains important intermediate (1R, 2R, 3aS, 9aS) -1- ((S) -3- hydroxy octyls) -2,3,3a, 4,9,9a- hexahydro -1H- rings
Pentane simultaneously [b] naphthalene -2,5- glycol, then reacted with the acetonitrile of halo or acetic acid esters, treprostinil that is obtained through hydrolysis.Agents useful for same
High volatility, synthesis cost is higher, and toxicity is larger, irritant to skin and eye, brings certain difficulty to amplification production, instead
Should it is excessively tediously long, be unfavorable for synthesizing on a large scale, can not largely synthesizing optical it is pure treprostinil that.
Due to the synthesis complexity of your molecule of your significance medically of treprostinil and treprostinil, there is an urgent need to
Exploitation is more applied to the effective ways of large-scale production.
The content of the invention
In view of the shortcomings of the prior art and the market demand, the synthetic method of Neil before being arranged the invention provides a koji are main
Step is wanted to include：It is oxidation of aldehydes to connect acetal, acetal hydro and hydration.Explored by many experiments, optimizing raw material proportioning so that anti-
Answer condition more gentle, shorten the reaction time, improve the yield of product, for high income up to 68%, technique is simple, and industrialization can be achieved
Large-scale production.
In a first aspect, the present invention provides the synthetic method of Neil before a koji arranges, comprise the following steps：
(1) acetal is connected：It is 1 by weight ratio:(2-4):((S) -3- hydroxyls are pungent by (1R, 2R, 3aS, the 9aS) -1- of (4-6)
Base) -2,3,3a, 4,9,9a- hexahydro -1H- pentamethylene simultaneously [b] naphthalene -2,5- glycol, Haloacetaldehydes dimethyl acetal and alkali soluble in appropriate
In solvent, heated, stirred in the presence of catalyst, being extracted, being washed, concentrate after obtain compound 1；
(2) acetal hydro：By bulking value (g/mL) than being 1:The compound 1 of (3-5) is dissolved in solvent after being mixed with acid
Stirring, it is evaporated under reduced pressure, filtration washing obtains compound 2；
(3) it is hydrated oxidation of aldehydes：It is (5-8) by weight ratio:It is (2-4) that 1 compound 2 is dissolved in volume ratio with potassium carbonate:1
Methanol is with hydrogen peroxide solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
According to the present invention, the chemical formula of the compound 1 is shown in formula I：
According to the present invention, the chemical formula of the compound 2 is as shown in Formula II：
Inventor find, if total recovery can be not only greatly reduced in the inappropriate reaction raw materials of additional proportion, can also produce compared with
More intermediate products, purity is influenceed, increase operating procedure.Therefore, the present invention passes through lot of experiments, draws said ratio, makes anti-
The total recovery answered reaches metastable higher level, maintains essentially in 63-65%, reaches as high as 68% or so.If beyond this
The scope limited is invented, total recovery substantially reduces, and causes the harmful effects such as the waste of reaction raw materials.
Preferably, the weight ratio described in step (1) is 1:(2-3):(4-5), such as can be 1:2:4、1:3:5 or 1:2:
5, preferably 1:3:5；
Preferably, the alkali described in step (1) is potassium hydroxide and/or potassium carbonate；
Preferably, the Haloacetaldehydes dimethyl acetal described in step (1) is that chloroacetaldehyde dimethyl acetal and/or bromoacetaldehyde contract
Dimethanol；
Preferably, the solvent described in step (1) is in dimethylformamide, 1-METHYLPYRROLIDONE or dimethyl sulfoxide (DMSO)
It is any or at least two mixture, such as can be the composition of dimethylformamide and 1-METHYLPYRROLIDONE, N- first
The combination of the composition or dimethylformamide, 1-METHYLPYRROLIDONE and dimethyl sulfoxide (DMSO) of base pyrrolidones and dimethyl sulfoxide (DMSO)
Thing, preferably dimethyl sulfoxide (DMSO)；
Preferably, the heating-up temperature described in step (1) is 50-65 DEG C, for example, can be 50 DEG C, 52 DEG C, 54 DEG C, 56 DEG C,
58 DEG C, 60 DEG C, 62 DEG C or 65 DEG C, preferably 65 DEG C；
Preferably, the extracts reagent described in step (1) is ethyl acetate and/or methanol；
Preferably, the catalyst described in step (1) is TBAB and/or KI；
Preferably, the bulking value (g/mL) described in step (2) is than being 1:(3-4), such as can be 1:3、1:3.5 or 1:
4, preferably 1:4；
Preferably, the solvent described in step (2) is any of ethanol, methanol or tetrahydrofuran or at least two group
Close, such as can be the combination of ethanol and methanol, the combination of methanol and tetrahydrofuran, the combination of ethanol and tetrahydrofuran or second
The combination of alcohol, methanol and tetrahydrofuran, preferably tetrahydrofuran；
Preferably, the acid described in step (2) is hydrochloric acid and/or trifluoroacetic acid；
Preferably, the detergent described in step (2) is water and/or methyl tertiary butyl ether；
Preferably, the weight ratio described in step (3) is (5-7):1, such as can be 5:1、6:1 or 7:1, preferably 7:1；
Preferably, the volume ratio described in step (3) is (2-3):1, such as can be 2:1、2.5:1 or 3:1, preferably 3:
1；
Preferably, the synthetic method of Neil, comprises the following steps before a koji arranges：
(1) acetal is connected：It is 1 by weight ratio:(2-4):((S) -3- hydroxyls are pungent by (1R, 2R, 3aS, the 9aS) -1- of (4-6)
Base) -2,3,3a, 4,9,9a- hexahydro -1H- pentamethylene simultaneously [b] naphthalene -2,5- glycol, Haloacetaldehydes dimethyl acetal and alkali soluble in appropriate
In solvent, 50-65 DEG C is heated in the presence of catalyst TBAB and/or KI, stirring, extraction, washes, is dense
Compound 1 is obtained after contracting；
The extracts reagent is ethyl acetate and/or methanol, and described alkali is potassium hydroxide and/or potassium carbonate, described
Haloacetaldehydes dimethyl acetal is chloroacetaldehyde dimethyl acetal and/or bromoacetaldehyde dimethyl acetal, and the solvent is dimethyl formyl
Any of amine, 1-METHYLPYRROLIDONE or dimethyl sulfoxide (DMSO) or at least two mixture；
(2) acetal hydro：By bulking value (g/mL) than being 1:Compound 1 and the hydrochloric acid and/or trifluoroacetic acid of (3-5) mix
It is dissolved in solvent and stirs after conjunction, is evaporated under reduced pressure, filters, being washed to obtain compound 2 with water and/or methyl tertiary butyl ether；
The solvent is any of ethanol, methanol or tetrahydrofuran or at least two combination；
(3) it is hydrated oxidation of aldehydes：It is (5-8) by weight ratio:It is (2-4) that 1 compound 2 is dissolved in volume ratio with potassium carbonate:1
Methanol is with hydrogen peroxide solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
Second aspect, the present invention provide a kind of basis Qu Lieqian Neils that as described in relation to the first aspect prepared by synthetic method.
Compared with prior art, the invention has the advantages that：
Synthetic method provided by the present invention is explored by many experiments, optimizing raw material proportioning so that reaction condition is more
Gently, shorten the reaction time, simplify reactions steps, improve the yield of product, it is extensive that industrialization can be achieved up to 68% in high income
Production, it can be that enterprise brings good economic benefit, possess wide prospect.
Embodiment
Further to illustrate the technological means and its effect of the invention taken, below in conjunction with being preferable to carry out for the present invention
Example further illustrates technical scheme, but the present invention is not limited in scope of embodiments.
Embodiment 1
(1) acetal is connected：It is 1 by weight ratio:3:5 (1R, 2R, 3aS, 9aS) -1- ((S) -3- hydroxy octyls) -2,3,
Simultaneously [b] naphthalene -2,5- glycol, chloroacetaldehyde dimethyl acetal and potassium hydroxide are dissolved in appropriate two to 3a, 4,9,9a- hexahydro -1H- pentamethylene
In methyl sulfoxide, 65 DEG C are heated in the presence of catalyst TBAB, stirring, ethyl acetate extraction, washing, concentration
After obtain compound 1；
(2) acetal hydro：By bulking value (g/mL) than being 1:4 compound 1 after mixed in hydrochloric acid with being dissolved in tetrahydrofuran
Middle stirring, it is evaporated under reduced pressure, filters, being washed with water to obtain compound 2；
(3) it is hydrated oxidation of aldehydes：It is 7 by weight ratio:1 compound 2 is dissolved in volume ratio for 3 with potassium carbonate:1 methanol with it is double
In the oxygen aqueous solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
Embodiment 2
(1) acetal is connected：It is 1 by weight ratio:2:4 (1R, 2R, 3aS, 9aS) -1- ((S) -3- hydroxy octyls) -2,3,
Simultaneously [b] naphthalene -2,5- glycol, bromoacetaldehyde dimethyl acetal and potassium carbonate are dissolved in appropriate diformazan to 3a, 4,9,9a- hexahydro -1H- pentamethylene
In base formamide, 50 DEG C are heated in the presence of catalyst KI, chemical combination is obtained after stirring, methanol extraction, washing, concentration
Thing 1；
(2) acetal hydro：By bulking value (g/mL) than being 1:3 compound 1 is dissolved in methanol after being mixed with trifluoroacetic acid
Middle stirring, it is evaporated under reduced pressure, filters, is washed to obtain compound 2 with methyl tertiary butyl ether；
(3) it is hydrated oxidation of aldehydes：It is 5 by weight ratio:1 compound 2 is dissolved in volume ratio for 2 with potassium carbonate:1 methanol with it is double
In the oxygen aqueous solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
Embodiment 3
(1) acetal is connected：It is 1 by weight ratio:4:6 (1R, 2R, 3aS, 9aS) -1- ((S) -3- hydroxy octyls) -2,3,
Simultaneously [b] naphthalene -2,5- glycol, bromoacetaldehyde dimethyl acetal and potassium hydroxide are dissolved in appropriate N- to 3a, 4,9,9a- hexahydro -1H- pentamethylene
In methyl pyrrolidone, be heated to 55 DEG C in the presence of catalyst TBAB, stirring, ethyl acetate extraction, washing,
Compound 1 is obtained after concentration；
(2) acetal hydro：By bulking value (g/mL) than being 1:5 compound 1 after mixed in hydrochloric acid with being dissolved in etoh solvent
Middle stirring, it is evaporated under reduced pressure, filters, is washed to obtain compound 2 with water and/or methyl tertiary butyl ether；
(3) it is hydrated oxidation of aldehydes：It is 8 by weight ratio:1 compound 2 is dissolved in volume ratio for 4 with potassium carbonate:1 methanol with it is double
In the oxygen aqueous solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
Embodiment 4
(1) acetal is connected：It is 1 by weight ratio:3:6 (1R, 2R, 3aS, 9aS) -1- ((S) -3- hydroxy octyls) -2,3,
Simultaneously [b] naphthalene -2,5- glycol, chloroacetaldehyde dimethyl acetal and potassium carbonate are dissolved in appropriate solvent to 3a, 4,9,9a- hexahydro -1H- pentamethylene
In dimethyl sulfoxide (DMSO), 62 DEG C are heated in the presence of catalyst KI, after stirring, ethyl acetate extraction, washing, concentration
To compound 1；
(2) acetal hydro：By bulking value (g/mL) than being 1:3.5 compound 1 is dissolved in molten after being mixed with trifluoroacetic acid
Stirred in agent tetrahydrofuran, be evaporated under reduced pressure, filter, being washed to obtain compound 2 with methyl tertiary butyl ether；
The solvent be ethanol, methanol or any of or at least two combination；
(3) it is hydrated oxidation of aldehydes：It is 5.5 by weight ratio:1 compound 2 is dissolved in volume ratio for 2.5 with potassium carbonate:1 methanol
With in hydrogen peroxide solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
Embodiment 5
(1) acetal is connected：It is 1 by weight ratio:3.6:4.8 (1R, 2R, 3aS, 9aS) -1- ((S) -3- hydroxy octyls) -
Simultaneously [b] naphthalene -2,5- glycol, bromoacetaldehyde dimethyl acetal and potassium carbonate are dissolved in right amount 2,3,3a, 4,9,9a- hexahydro -1H- pentamethylene
In solvent dimethylformamide, be heated to 57 DEG C in the presence of catalyst TBAB, stirring, methanol extraction, washing,
Compound 1 is obtained after concentration；
(2) acetal hydro：By bulking value (g/mL) than being 1:3.7 compound 1 is dissolved in molten after being mixed with trifluoroacetic acid
Stirred in agent methanol, be evaporated under reduced pressure, filter, being washed to obtain compound 2 with methyl tertiary butyl ether；
(3) it is hydrated oxidation of aldehydes：It is 5.9 by weight ratio:1 compound 2 is dissolved in volume ratio for 3.3 with potassium carbonate:1 methanol
With in hydrogen peroxide solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
Comparative example 1
Compared with Example 1, except the weight ratio of step (1) is changed to 1:1:Outside 1, other conditions are same as Example 1.
Comparative example 2
Compared with Example 1, except the weight ratio of step (1) is changed to 1:6:Outside 8, other conditions are same as Example 1.
Comparative example 3
Compared with Example 1, except bulking value (g/mL) ratio of step (2) is changed to 1:Outside 1, other conditions and embodiment 1
It is identical.
Comparative example 4
Compared with Example 1, except bulking value (g/mL) ratio of step (2) is changed to 1:Outside 10, other conditions and embodiment 1
It is identical.
Comparative example 5
Compared with Example 1, except the weight ratio of step (3) is changed to 4:1, volume ratio is changed to 1:Outside 1, other conditions and reality
It is identical to apply example 1.
Comparative example 6
Compared with Example 1, except the weight ratio of step (3) is changed to 10:1, volume ratio is changed to 6:Outside 1, other conditions with
Embodiment 1 is identical.
Comparative example 7
Compared with Example 1, in addition to the temperature of step (1) is 30 DEG C, other conditions are same as Example 1.
Overall yield of reaction refers to the number of the product of output by chemically reacting, and theoretical yield refers to perfectly balanced
In reaction can output maximum product volume, but actual production is often less than theoretical yield., can be with to embody reaction efficiency
Total recovery is calculated using following formula：Total recovery %=(actual production/theoretical yield) × 100%.According to above formula,
The total recovery of embodiment and comparative example is calculated, as a result as shown in table 1.
Table 1
| Sample | Yield (%) |
| Embodiment 1 | 68 |
| Embodiment 2 | 65 |
| Embodiment 3 | 63 |
| Embodiment 4 | 65 |
| Embodiment 5 | 64 |
| Comparative example 1 | 53 |
| Comparative example 2 | 54 |
| Comparative example 3 | 56 |
| Comparative example 4 | 52 |
| Comparative example 5 | 55 |
| Comparative example 6 | 54 |
| Comparative example 7 | 53 |
Analyzed from table 1, the embodiment 1-5 institutes of raw material proportioning and reaction condition in scope provided by the present invention
The yield of the sample of synthesis is held in more than 63%, and the sample yield of wherein embodiment 1 is up to 68%.And comparative example 1-
After 6 raw material proportioning over range, after the reaction condition over range of comparative example 7, sample yield declines to a great extent.
In summary, on the basis of existing technology, explored by many experiments, optimizing raw material proportioning so that reaction bar
Part is more gentle, shortens the reaction time, improves the yield of product, embodiment 1 is optimal case, and the sample high income of synthesis reaches
68%, product yield is significantly affected after raw material proportioning and reaction condition over range.Present invention process is simple, and industrialization can be achieved
Large-scale production, it can be that enterprise brings good economic benefit, possess wide prospect.
Applicant states that the present invention illustrates the method detailed of the present invention, but not office of the invention by above-described embodiment
It is limited to above-mentioned method detailed, that is, does not mean that the present invention has to rely on above-mentioned method detailed and could implemented.Art
Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention
Addition, selection of concrete mode etc., within the scope of all falling within protection scope of the present invention and disclosing.
Claims (10)
1. your synthetic method of a kind of treprostinil, it is characterised in that comprise the following steps：
(1) acetal is connected：It is 1 by weight ratio:(2-4):(1R, 2R, 3aS, the 9aS) -1- ((S) -3- hydroxy octyls) of (4-6) -
2,3,3a, 4,9,9a- hexahydro -1H- pentamethylene simultaneously [b] naphthalene -2,5- glycol, Haloacetaldehydes dimethyl acetal and alkali soluble in appropriate solvent
In, heated, stirred in the presence of catalyst, being extracted, being washed, concentrate after obtain compound 1；
(2) acetal hydro：By bulking value (g/mL) than being 1:The compound 1 of (3-5) is dissolved in solvent after being mixed with acid to be stirred,
It is evaporated under reduced pressure, filtration washing obtains compound 2；
(3) it is hydrated oxidation of aldehydes：It is (5-8) by weight ratio:It is (2-4) that 1 compound 2 is dissolved in volume ratio with potassium carbonate:1 methanol
With in hydrogen peroxide solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
2. synthetic method according to claim 1, it is characterised in that the chemical formula of the compound 1 is shown in formula I：
Preferably, the chemical formula of the compound 2 is as shown in Formula II：
3. synthetic method according to claim 1, it is characterised in that the weight ratio described in step (1) is 1:(2-3):(4-
5), preferably 1:3:5；
Preferably, the alkali described in step (1) is potassium hydroxide and/or potassium carbonate；
Preferably, the Haloacetaldehydes dimethyl acetal described in step (1) is chloroacetaldehyde dimethyl acetal and/or bromoacetaldehyde contracting diformazan
Alcohol；
Preferably, the solvent described in step (1) is any in dimethylformamide, 1-METHYLPYRROLIDONE or dimethyl sulfoxide (DMSO)
Kind or at least two mixture, preferably dimethyl sulfoxide (DMSO).
4. synthetic method according to claim 1, it is characterised in that the heating-up temperature described in step (1) is 50-65 DEG C,
Preferably 65 DEG C；
Preferably, the extracts reagent described in step (1) is ethyl acetate and/or methanol；
Preferably, the catalyst described in step (1) is TBAB and/or KI.
5. synthetic method according to claim 1, it is characterised in that bulking value (g/mL) ratio described in step (2) is
1:(3-4), preferably 1:4；
Preferably, the solvent described in step (2) is any of ethanol, methanol or tetrahydrofuran or at least two combination,
Preferably tetrahydrofuran.
6. synthetic method according to claim 1, it is characterised in that the acid described in step (2) is hydrochloric acid and/or trifluoro second
Acid；
Preferably, the detergent described in step (2) is water and/or methyl tertiary butyl ether.
7. synthetic method according to claim 1, it is characterised in that the weight ratio described in step (3) is (5-7):1, it is excellent
Elect 7 as:1.
8. synthetic method according to claim 1, it is characterised in that the volume ratio described in step (3) is (2-3):1, it is excellent
Elect 3 as:1.
9. according to the synthetic method any one of claim 1-8, it is characterised in that comprise the following steps：
(1) acetal is connected：It is 1 by weight ratio:(2-4):(1R, 2R, 3aS, the 9aS) -1- ((S) -3- hydroxy octyls) of (4-6) -
2,3,3a, 4,9,9a- hexahydro -1H- pentamethylene simultaneously [b] naphthalene -2,5- glycol, Haloacetaldehydes dimethyl acetal and alkali soluble in appropriate solvent
In, 50-65 DEG C, after stirring, extraction, washing, concentration is heated in the presence of catalyst TBAB and/or KI
Obtain compound 1；
Described extracts reagent is ethyl acetate and/or methanol, and described alkali is potassium hydroxide and/or potassium carbonate, described halogen
Be chloroacetaldehyde dimethyl acetal and/or bromoacetaldehyde dimethyl acetal for dimethylacetal, the solvent be dimethylformamide,
Any of 1-METHYLPYRROLIDONE or dimethyl sulfoxide (DMSO) or at least two mixture；
(2) acetal hydro：By bulking value (g/mL) than being 1:After the compound 1 of (3-5) mixes with hydrochloric acid and/or trifluoroacetic acid
It is dissolved in solvent and stirs, is evaporated under reduced pressure, filters, being washed to obtain compound 2 with water and/or methyl tertiary butyl ether；
Described solvent is any of ethanol, methanol or tetrahydrofuran or at least two combination；
(3) it is hydrated oxidation of aldehydes：It is (5-8) by weight ratio:It is (2-4) that 1 compound 2 is dissolved in volume ratio with potassium carbonate:1 methanol
With in hydrogen peroxide solution, treprostinil that is obtained after stirring, pressurization evaporative filtration.
A kind of 10. Qu Lieqian Neils prepared according to any one of 1 claim 1-9 synthetic method.
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| CN201711041330.5A CN107602376A (en) | 2017-10-30 | 2017-10-30 | The synthetic method of Neil before one koji arranges |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151151A (en) * | 2014-07-30 | 2014-11-19 | 天泽恩源（天津）医药技术有限公司 | Novel synthesis method of treprostinil |
| WO2014203278A2 (en) * | 2013-06-19 | 2014-12-24 | Msn Laboratories Private Limited | NOVEL PROCESS FOR THE PREPARATION OF (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-HEXAHYDRO-2-HYDROXY-1-[(3S)-3-HYDROXYOCTYL]-1H-BENZ[f]INDEN-5-YL]OXY]ACETIC ACID |
| US20160289158A1 (en) * | 2013-11-13 | 2016-10-06 | Cayman Chemical Company Incorporated | Amine Salts of a Prostacyclin Analog |
-
2017
- 2017-10-30 CN CN201711041330.5A patent/CN107602376A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014203278A2 (en) * | 2013-06-19 | 2014-12-24 | Msn Laboratories Private Limited | NOVEL PROCESS FOR THE PREPARATION OF (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-HEXAHYDRO-2-HYDROXY-1-[(3S)-3-HYDROXYOCTYL]-1H-BENZ[f]INDEN-5-YL]OXY]ACETIC ACID |
| US20160289158A1 (en) * | 2013-11-13 | 2016-10-06 | Cayman Chemical Company Incorporated | Amine Salts of a Prostacyclin Analog |
| CN104151151A (en) * | 2014-07-30 | 2014-11-19 | 天泽恩源（天津）医药技术有限公司 | Novel synthesis method of treprostinil |
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Application publication date: 20180119 |