CA1106410A - Process for the preparation of 1-(4-isopropylmercapto- phenyl)-2-n. octylaminopropanol - Google Patents
Process for the preparation of 1-(4-isopropylmercapto- phenyl)-2-n. octylaminopropanolInfo
- Publication number
- CA1106410A CA1106410A CA306,545A CA306545A CA1106410A CA 1106410 A CA1106410 A CA 1106410A CA 306545 A CA306545 A CA 306545A CA 1106410 A CA1106410 A CA 1106410A
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- isopropylmercapto
- octylaminopropanol
- preparation
- fact
- 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.)
- Expired
Links
- ZJNGCHWVIQXKRC-UHFFFAOYSA-N 1-(octylamino)propan-1-ol Chemical compound CCCCCCCCNC(O)CC ZJNGCHWVIQXKRC-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- -1 4-isopropylmercapto-phenyl group Chemical group 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 1
- 239000012279 sodium borohydride Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BFCDFTHTSVTWOG-YLJYHZDGSA-N (1S,2R)-2-(octylamino)-1-[4-(propan-2-ylthio)phenyl]-1-propanol Chemical compound CCCCCCCCN[C@H](C)[C@@H](O)C1=CC=C(SC(C)C)C=C1 BFCDFTHTSVTWOG-YLJYHZDGSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960003967 suloctidil Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
TITLE OF THE INVENTION
"A PROCESS FOR THE PREPARATION OF 1-(4-ISOPROPYLMERCAPTO-PHENYL)-2-n.OCTYLAMINOPROPANOL"
ABSTRACT OF THE DISCLOSURE
A process for the preparation of 1-(4-isopropyl-mercapto-phenyl)-2-n.octylaminopropanol comprising the reduction of 1-(4-isopropylmercapto-phenyl)-1-(trimethyl-silyloxi)-2-n.octylamino-propene (II) and the acid hydrolysis of the re-duction mixture.
"A PROCESS FOR THE PREPARATION OF 1-(4-ISOPROPYLMERCAPTO-PHENYL)-2-n.OCTYLAMINOPROPANOL"
ABSTRACT OF THE DISCLOSURE
A process for the preparation of 1-(4-isopropyl-mercapto-phenyl)-2-n.octylaminopropanol comprising the reduction of 1-(4-isopropylmercapto-phenyl)-1-(trimethyl-silyloxi)-2-n.octylamino-propene (II) and the acid hydrolysis of the re-duction mixture.
Description
2~ 10 The invention relates to a new process for preparing 1-(4-isopropylmercapto-phenyl)-2-n.oc-tyl~minopropanol of the formula I
C~-CH-NH-n.C8~17 which is a compound endowed with interesting therapeutic pro~
perties (it is ~n~wn as "Suloctidil"). In the pr~ art, the compound (I) i9 prepared from 4-isopropylmercapto-propiopheno ne, usually through the corresponding bromoketone, which i9 reacted with nOoctylamine, the 80 obtained 1~(4-i~opropyl-mercapto-phenyl)-2-n.octylamino-propanone-1 being then reducec to the end product (I).
~ ho preparation of the intermediate bromoketone presents some disadvantages due, on one side~ to the simultaneous for mation (even though to a small extent) of other bromoderivati~
~0.8, on the other to the fact that bromoketone i~ an aggressi ve compound and~ as all the compounds o~ this kînd~ it is a strong allergenic agent~ ~he following reaction with n.octyla mine and the final reductio~ ~re characterized by poor yields , i41(~
both if the intermediate octyl~minoketone is isolated and, and even worse, if the two stages are per*ormed in direct suc cession.
The other methods described for the preparation of the com-pound (I) lack of practical intere~t, eitherfor the tri~ling yields of the corresponding reactionsJ or for the excessive cost of the involved reagents.
I It has now been found that it is possible to obtain the ¦ compound (I) with very good yields and without using toxic or expensive intermediates if 1-(4-i~opropylmercapto-phenyl)-1-(trimeth~l-silyloxy)-2-n.octylamino-propene (II) is reduced and the so obtained reaction mixture iæ direetly hydrolysed in acid medium, according to the scheme:
, .
Ir (CH3)3Si-O-C=C_CH3 1)Na~H4 (I) ; NH 2)HCl (II) where Ar repre~onts the 4-i~opropyl~ercapto-phenyl group~
The intermediate (II) i5 ea~ily obtainable ~rom 4-isopro pylmercapto-propiophenone (III) through the ~cheme of reac-i tion~ b low:
~ 6 ~ ~0 ij ~ 4 ) I
I lr (CH3)3SiCl Ar ¦ ~) C0-CH -CH ~ (CH3)3Si-0-C-CH-CH3 ;
(III~ (IV) b) (IV) N chloro-~uccinimide ~CH ) 3i-0-C~-CH ;
~ 3 3 3 (V) c) (V) B 17 2 (II) where Ar has the above mentioned me~ning~ Both the three reactions a), b) a~d c) above indicated and the final trans-form~tion of (II) in the end product oocur with high yields and without any difficulty.
It ha~ furthermore been found that the final compound (1~
can be obtained in a ver~ ~imple and advantageou~ way for the production on industrial ~oale directly from the ketons (III) without i~olating any of the intermediatee (IV~, (V) and (II) which are ~ucca~ ely formed. ~he compol~nd (I) thus obtained .
ha~ noteworthy dagree of purity~
The prooes~ of this invention will be explained by the fol-lowing example~ relatsd to the pre~err~d embodiment, i.e.
without i801ating the intermediate~
1~13Ç6~10 ~ - 5 -EXAMPLE
To a solution of 120 gr (1 1 moles) of trimethylsilylchlo-rlde and 95 gr (1.1 moles) of triethylamine in 750 ml of N,N-dimethylformamide, 208 gr (1 mole) of 4-isopropylmercapto propiophenone are added. ~he mixture i8 refluxed for 36 hours then about 500 ml of N,N-dimethylformamide are distilled under vacuum and the residue is treated with 2 liters of hexane; the solution i6 washed with two portions of 1200 ml of an aqueous N~C03-saturated solution, then (rapidly and in the cool) with 1 liter of 1.5-molar Hl, then again with 1 ; liter o~ NaH~03-saturated 601ution. ~he organic layer is eva-porated to dryness and the residue is dissolved in 800 ml of CHC13.
~o the chloroformic solution, 90 ml of pyridine and 130 gr (1 mole) of N-chlorosuccinimide ~re added. ~he mixture is stirred at room temperature for 24 hours; th~ the 80 o~tained solution of 1-(4-isopropylmer¢apto-phenyl)-1-(trimethylsilyl oxy-methyl)-2-chloropropene (V) is treated with a solution of 130 gr (1 mole~ of n.octylamine and 86 gr (1 mole) of trieth~
; ~20 lamine i~ 400 ml of CHC13. ~he mixture is stirred at 40C for
C~-CH-NH-n.C8~17 which is a compound endowed with interesting therapeutic pro~
perties (it is ~n~wn as "Suloctidil"). In the pr~ art, the compound (I) i9 prepared from 4-isopropylmercapto-propiopheno ne, usually through the corresponding bromoketone, which i9 reacted with nOoctylamine, the 80 obtained 1~(4-i~opropyl-mercapto-phenyl)-2-n.octylamino-propanone-1 being then reducec to the end product (I).
~ ho preparation of the intermediate bromoketone presents some disadvantages due, on one side~ to the simultaneous for mation (even though to a small extent) of other bromoderivati~
~0.8, on the other to the fact that bromoketone i~ an aggressi ve compound and~ as all the compounds o~ this kînd~ it is a strong allergenic agent~ ~he following reaction with n.octyla mine and the final reductio~ ~re characterized by poor yields , i41(~
both if the intermediate octyl~minoketone is isolated and, and even worse, if the two stages are per*ormed in direct suc cession.
The other methods described for the preparation of the com-pound (I) lack of practical intere~t, eitherfor the tri~ling yields of the corresponding reactionsJ or for the excessive cost of the involved reagents.
I It has now been found that it is possible to obtain the ¦ compound (I) with very good yields and without using toxic or expensive intermediates if 1-(4-i~opropylmercapto-phenyl)-1-(trimeth~l-silyloxy)-2-n.octylamino-propene (II) is reduced and the so obtained reaction mixture iæ direetly hydrolysed in acid medium, according to the scheme:
, .
Ir (CH3)3Si-O-C=C_CH3 1)Na~H4 (I) ; NH 2)HCl (II) where Ar repre~onts the 4-i~opropyl~ercapto-phenyl group~
The intermediate (II) i5 ea~ily obtainable ~rom 4-isopro pylmercapto-propiophenone (III) through the ~cheme of reac-i tion~ b low:
~ 6 ~ ~0 ij ~ 4 ) I
I lr (CH3)3SiCl Ar ¦ ~) C0-CH -CH ~ (CH3)3Si-0-C-CH-CH3 ;
(III~ (IV) b) (IV) N chloro-~uccinimide ~CH ) 3i-0-C~-CH ;
~ 3 3 3 (V) c) (V) B 17 2 (II) where Ar has the above mentioned me~ning~ Both the three reactions a), b) a~d c) above indicated and the final trans-form~tion of (II) in the end product oocur with high yields and without any difficulty.
It ha~ furthermore been found that the final compound (1~
can be obtained in a ver~ ~imple and advantageou~ way for the production on industrial ~oale directly from the ketons (III) without i~olating any of the intermediatee (IV~, (V) and (II) which are ~ucca~ ely formed. ~he compol~nd (I) thus obtained .
ha~ noteworthy dagree of purity~
The prooes~ of this invention will be explained by the fol-lowing example~ relatsd to the pre~err~d embodiment, i.e.
without i801ating the intermediate~
1~13Ç6~10 ~ - 5 -EXAMPLE
To a solution of 120 gr (1 1 moles) of trimethylsilylchlo-rlde and 95 gr (1.1 moles) of triethylamine in 750 ml of N,N-dimethylformamide, 208 gr (1 mole) of 4-isopropylmercapto propiophenone are added. ~he mixture i8 refluxed for 36 hours then about 500 ml of N,N-dimethylformamide are distilled under vacuum and the residue is treated with 2 liters of hexane; the solution i6 washed with two portions of 1200 ml of an aqueous N~C03-saturated solution, then (rapidly and in the cool) with 1 liter of 1.5-molar Hl, then again with 1 ; liter o~ NaH~03-saturated 601ution. ~he organic layer is eva-porated to dryness and the residue is dissolved in 800 ml of CHC13.
~o the chloroformic solution, 90 ml of pyridine and 130 gr (1 mole) of N-chlorosuccinimide ~re added. ~he mixture is stirred at room temperature for 24 hours; th~ the 80 o~tained solution of 1-(4-isopropylmer¢apto-phenyl)-1-(trimethylsilyl oxy-methyl)-2-chloropropene (V) is treated with a solution of 130 gr (1 mole~ of n.octylamine and 86 gr (1 mole) of trieth~
; ~20 lamine i~ 400 ml of CHC13. ~he mixture is stirred at 40C for
3 hours; the precipitated salts are filtered off and the sol-vent is evaporated under vaouum.
~he re~idue (which is a thiek reddish oil) is dissolved in 700 ml of methanol, then treated under stirring with a solu-~- ~
~ tion of 30 gr of NaEH4 in 2QO ml of 5-normal aqueous NaOH;
,~ i ,., ~., ~ :
, ' : . : '.' ~
~ ' :
1~6~1~
during this reaction the temperature is maintained at 20-30C.
After the addition, stirring is continued for 30 minutes, then 10% HCl is added until pH 1-2. The mixture is stirred for 2 hours, the so formed 1-(4-isopropyl-mercapto-phenyl)-2-n.octylaminopropanol hydrochloride is filtered by suction and washed with diisopropylether.
After drying 224 gr of said hydrochloride are obtained, by treating with Na2OC3-solution the corresponding base (I) is formed (198 gr), m.p. 64-65C; the compound is sub-stantially unitary in thin layer chromatrography.
r~
.
~he re~idue (which is a thiek reddish oil) is dissolved in 700 ml of methanol, then treated under stirring with a solu-~- ~
~ tion of 30 gr of NaEH4 in 2QO ml of 5-normal aqueous NaOH;
,~ i ,., ~., ~ :
, ' : . : '.' ~
~ ' :
1~6~1~
during this reaction the temperature is maintained at 20-30C.
After the addition, stirring is continued for 30 minutes, then 10% HCl is added until pH 1-2. The mixture is stirred for 2 hours, the so formed 1-(4-isopropyl-mercapto-phenyl)-2-n.octylaminopropanol hydrochloride is filtered by suction and washed with diisopropylether.
After drying 224 gr of said hydrochloride are obtained, by treating with Na2OC3-solution the corresponding base (I) is formed (198 gr), m.p. 64-65C; the compound is sub-stantially unitary in thin layer chromatrography.
r~
.
Claims (3)
1. Process for preparing 1-(4-isopropylmercapto-phenyl)-2-n.octylaminopropanol (I), characterized by the fact that 1-(4-isopropylmercapto-phenyl)-1-(trimethyl-silyloxy)-2-n.octylamino-propene (II) is reduced with sodium boro-hydride and successively hydrolyzed in acid medium, according to the scheme:
(II) (I) where Ar represents the 4-isopropylmercapto-phenyl group.
(II) (I) where Ar represents the 4-isopropylmercapto-phenyl group.
2. Process as claimed in claim 1, characterized by the fact that the compound (II) is obtained according to the following reactions:
(II) where Ar has the above mentioned meaning.
(II) where Ar has the above mentioned meaning.
3. Process as claimed in claim 1 and 2, characterized by the fact that 1-(4-isopropylmercapto-phenyl)-2-n.octyl-aminopropanol is directly obtained from 4-isopropyl-mercapto-propiophenone, through the above indicated reactions, without isolating the intermediate compounds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT25580/77A IT1082122B (en) | 1977-07-11 | 1977-07-11 | PROCESS FOR THE PREPARATION OF 1- (4-ISOPROPILMERCAPTO-FENYL) -2-N.OCTYLAMINE-PROPANOL |
| IT25580A/77 | 1977-07-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1106410A true CA1106410A (en) | 1981-08-04 |
Family
ID=11217152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA306,545A Expired CA1106410A (en) | 1977-07-11 | 1978-06-29 | Process for the preparation of 1-(4-isopropylmercapto- phenyl)-2-n. octylaminopropanol |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5419927A (en) |
| AT (1) | AT356080B (en) |
| CA (1) | CA1106410A (en) |
| CH (1) | CH629482A5 (en) |
| IT (1) | IT1082122B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT380873B (en) * | 1980-12-24 | 1986-07-25 | Continental Pharma | METHOD FOR PRODUCING 1- (4-ISOPROPYLTHIOPHENYL) -2-N.OCTYL-AMINO-PROPANOL, ITS ACID ADDITION SALTS AND ESTERS |
| LU83039A1 (en) * | 1980-12-24 | 1982-07-07 | Continental Pharma | METHODS OF SYNTHESIS OF 1- (4 ISOPROPYLTHIOPHENYL) -2-N OCTYLAMINOPROPANOL |
| AT380874B (en) * | 1980-12-24 | 1986-07-25 | Continental Pharma | METHOD FOR PRODUCING 1- (4-ISOPROPYLTHIOPHENYL) -2-N.OCTYL-AMINO-PROPANOL, ITS ACID ADDITION SALTS AND ESTERS |
-
1977
- 1977-07-11 IT IT25580/77A patent/IT1082122B/en active
-
1978
- 1978-06-22 CH CH678578A patent/CH629482A5/en not_active IP Right Cessation
- 1978-06-29 CA CA306,545A patent/CA1106410A/en not_active Expired
- 1978-07-04 JP JP8185878A patent/JPS5419927A/en active Granted
- 1978-07-05 AT AT486078A patent/AT356080B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| CH629482A5 (en) | 1982-04-30 |
| IT1082122B (en) | 1985-05-21 |
| JPS5725545B2 (en) | 1982-05-29 |
| ATA486078A (en) | 1979-09-15 |
| AT356080B (en) | 1980-04-10 |
| JPS5419927A (en) | 1979-02-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |