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Synthesis and Characterization of Potential Impurity of Muscle Relaxant Drug

Carisoprodol

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Journal of Chemistry and Chemical Sciences, Vol.7(4), 352-360, April 2017 ISSN 2229-760X (Print)
(An International Research Journal), www.chemistry-journal.org ISSN 2319-7625 (Online)

Synthesis and Characterization of Potential Impurity of

Muscle Relaxant Drug Carisoprodol
K. Arun Kumar, V S Lakshmipathi, Suman Meenakshi and M. Hari Balakrishnan

Strides Shasun Research Centre, 27, Vandaloor,

Melakottaiyur Post, Keelakottaiyur Villiage, Chennai-600127, INDIA
email:arunkumar.962@rediffmail.com.

(Received on: April 7, Accepted: April 27, 2017)

ABSTRACT

The present paper describes the identification, synthesis and characterization

of a new process related impurity of carisoprodol drug substance observed during the
optimization and later during its bulk synthesis. The process developed in lab was
efficient to remove all impurities except an impurity consistently observed at 0.14 %
level. The structure of the impurity was tentatively assigned on the basis of
fragmentation pattern in LC-MS as Carbamic acid 2-isopropylcarbamoyloxymethyl-
2-methyl-pent-3-enyl ester which is not reported in U.S. pharmacopeia. The impurity
was synthesised, characterised and co-injected with carisoprodol sample to confirm
the retention time in HPLC.

Keywords: Carbamic acid 2-isopropylcarbamoyloxymethyl-2-methyl-pent-3-enyl

ester, muscle relaxant, potential impurity, Co-injection.

INTRODUCTION

Carisoprodol (1) is chemically known as (RS)-2-{[(amino carbonyl) oxy] methyl}-2-

methyl pentyl isopropyl carbamate possessing tranquilizing and skeletal muscle relaxant
properties, which is a centrally acting muscle relaxant, with analgesic properties, making it a
popular drug of abuse. Carisoprodol is a dicarbamate, centrally acting, oral skeletal muscle
relaxant whose chief application is in the treatment of acute muscular spasm associated with
craniomandibular disorder, lumbago, sciatica, and other lower back syndromes1.
According to (ICH) guidelines on impurities in new drug substances, products, and
residual solvents, the level of total impurities must be reduced typically to less than 1.0%, and
each individual impurity of 0.1% or above must be identified2. The safety and efficacy of drug
substance depends on the impurity profiling with respect to identification and quantification
and now it is receiving vital attention from regulatory authorities. The identification and

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synthesis has become a challenging task for the organic chemist. Since it is difficult to identify
and control the impurities at acceptable level, extra purification is required there by making
the process less competitive.
Generally it makes it even more difficult for the organic chemist to design a synthesis
for the critical impurities, which are not reported in the literature. The development of drug
substance is incomplete without understanding the impurity profile involved in the process
and this impurity profiling study will be of immense help for organic chemists regarding the
potential impurity of carisoprodol API drug substance.
The literature survey on carisoprodol revealed that there are 4 process related
impurities reported in U.S. pharmacopeia, which are identified and synthesized 3. Other than
these known impurities an unknown impurity was observed at 0.14% when analysed by USP
HPLC method during the lab optimization and commercial manufacturing of our process [ref].
As a result it was a regulatory requirement to isolate, synthesise and characterize the process
impurity. This report describes the identification, synthesis (or isolation), and characterization
of the carisoprodol impurity and a mechanistic rationale for the formation of the impurity. To
the best of our knowledge, there is no commercial vendor for this new impurity and also there
is no synthesis reported in literature.
Process Impurity. The process for synthesis of Carisoprodol is shown in scheme-1.
Thecondensation of 2-methyl-2-propyl-propane-1, 3-diol (MPPD) 2 with dimethyl carbonate
and base as catalyst gives compound 3. The reaction of cyclic dioxanone 3 with isopropyl
amine resulted in mono isopropyl carbamate 4. The carbamate 4 is carbamylated with sodium
cyanate and dry HCl followed by recrystallization from methanol water to afford Carisoprodol (1).
The developed process is efficient to remove all reported impurities, but it resulted in
a process impurity routinely observed in the API in levels greater than 0.10% (HPLC area).
Accordingly, the impurity was identified, synthesized and characterized with the aid of modern
techniques.

Scheme-1
RESULTS AND DISCUSSION
A comprehensive study was undertaken to identify the unknown impurity by LC-MS
method, followed by confirmation through synthesis of unknown impurity, and by
characterization of the prepared impurity based on modern spectroscopic techniques.
Presence of this unknown impurity was detected by HPLC in synthesized
Carisoprodol (1) and the mechanistic aspect behind the formation of the impurity was studied.
The impurity was controlled by improving reaction conditions and developed recrystallization
techniques to the best of knowledge, identification, synthesis and characterization of the above
said new process-related impurity was not reported so far.

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The new process related impurity appeared at RRT 0.67 at polar end of the
chromatogram compared to Carisoprodol. We intended to identify the possible structure by
considering the molecular weights (by LCMS), followed by their synthesis and confirming
through correlating these with the impurities forming in the reaction (by HPLC). The LC-MS
details of unknown impurities were given in figure 1.
The mass spectrum recorded for the impurity in positive mode by LC-MS showed a
molecular ion peak at m/z 259 [M + H] + indicating the molecular weight of the impurity as
258. Also it contained characteristic fragments at m / z values 156, 198.
Whereas the mass spectrum of parent ion showed a molecular ion peak at m / z 261
[M+H] + corresponding to the molecular weight of 260 with fragments at m / z values 158,
176, 200. While reviewing the data we observed that the impurity had a molecular weight that
was 2 amu less than the parent ion peak. Based on the molecular weight it has been speculated
that the impurity could be an olefin compound. The probable structures are as follows.

5 6
Figure-1
From the above two compounds possible structure might be 5 as the more substituted
double bond is stable compared to less substituted double bond. The above speculated
compound is similar to the impurity observed in Meprabamate4.
The proposed impurity was synthesized by following Scheme 2, and all the spectral
data confirm the structure. Chromatographic studies (HPLC) with varying the concentration
of impurity were also conducted and concluded that the same impurity existed in carisoprodol.
Possible Synthetic Approach for compound - 9:

Scheme-2

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As per the above proposed scheme, diethyl malonate 7 was reacted with
propionaldehyde with acetic anhydride as catalyst to give compound 8 5. The reaction of
Propylidene diethyl ester 8 with methyl iodide and LDA resulted in rearrangement of double
bond to give the propenyl ester compound 9 6, followed by reduction of ester with excess
DiBAL to furnish the desired diol 10 in moderate yield.
The critical formation of cyclic carbonate from diol 10 with dimethyl carbonate and
sodium methoxide base was attempted under various reported conditions [ref], but it failed to
give us the desired cyclic carbonate 11. Instead the uncyclized mono ester was isolated in most
of the cases (Scheme 3). Our efforts to cyclize 10 under various conditions using various metal
alkoxides, at elevated temperature proved to be ineffectual, consequently all cases resulted in
polymer product7.
OH O
DMC
O
120 - 150 ° C O
OH

Triphosgene - 78 °C
DCM

O
O
O

Scheme-3

Fortunately the cyclization worked with triphosgene using pyridine as base in

dichloromethane. The reaction went smoothly to afford cyclic carbonate 11 with reasonable
yield8.
Optimization of cyclization condition
Reagents Conditions Time Yield
DMC Toluene, NaOMe 120°C 15 h -----
DEC Toluene, NaOEt, 120°C 12 h -----
K2CO3 DMF, 120°C 15 h -----
TPP DCM, - 78°C 1.0 h 70%
Once we had critical intermediate in our hand, we went ahead for the ring opening
with neat diisopropyl amine at 90 °C to furnish the monocarbamate 12 9. And finally
carbamylation of hydroxyl group by sodium cyanate and dry HCl in toluene to afford the
targeted compound 5 in moderate yield 9.

Characterization of both impurities

The ESI-MS spectrum of olefin monocarbamate impurity 12 showed a protonated
molecule peak at m/z 216.1 (M + H) +, indicating the molecular mass of this impurity to be
215.1, which is 45 amu less than that of Carisoprodol. In the 1H NMR spectrum of this

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impurity, the doublet and multiplet signal appearing at δ 5.41 ppm and 5.46 ppm is evidence
for the presence of olefin protons, whereas the signals at δ 5.41 ppm and 5.46 ppm
corresponding to the olefin proton was absent in carisoprodol, it was further confirmed by the
13C spectra, which displayed a shortage of olefin carbon signals at δ δ125.46, δ133.4 ppm.
Based on the above spectral data, the molecular formula of impurity was confirmed as
C11H21NO3 and the corresponding structure was characterized as Isopropyl-carbamic acid 2-
hydroxymethyl-2-methyl-pentyl ester
The ESI-MS spectrum of carisoprodol olefin impurity 5 showed a protonated
molecule peak at m/z 259.1 (M + H) +, indicating the molecular mass of this impurity to be
258.1, which is 2 amu less than that of Carisoprodol. In the 1H NMR spectrum of this impurity,
the doublet and mutiplet signal appearing at δ 5.41 ppm and 5.46 ppm is evidence for the
presence of olefin protons, whereas the signals at δ 5.41 ppm and 5.46 ppm corresponding to
the olefin proton was absent in carisoprodol, it was further confirmed by the 13C spectra,
which displayed a shortage of olefin carbon signals at δ124.4, δ131.7ppm. Based on the above
spectral data, the molecular formula of impurity was confirmed as C12H22N2O4 and the
corresponding structure was characterized as Carbamic acid 2-isopropylcarbamoyloxymethyl-
2-methyl-pent-3-enyl ester
Formation of impurity
Carisoprodol was synthesized using 2-methyl-2-propyl-propane-1, 3-diol (MPPD) as
the starting material. It is proposed that the presence of 2- hydroxymethyl-2-methyl-pentane-
1, 3-diol as impurity in Diol can undergo simultaneous bis-carbamylation and dehydration to
give carbamic acid-2-carbamoyloxymethyl-2-methyl-pent-3-enyl ester which is the
carisoprodol olefin impurity found at 0.67 RRT in the HPLC-UV method. As per the strategy,
the triol was prepared from diethyl methyl malonate as starting material, and analysed by GC
in comparison with diol (KSM). The relevant triol was not detected in GC analysis.
Mechanism

After careful observation of LC-MS of compound 4 we noticed a molecular ion peak

at m/z 216 [M + H] + indicating the molecular weight of the impurity as 215. Whereas the
mass spectrum of parent ion showed a molecular ion peak at m / z 218 [M+H] + corresponding
to the molecular weight of 217 with fragments 158, 200 again indicating 2 amu less than the
parent ion peak.
Then our attention shifted to analyse and compare the corresponding olefin impurities
prepared from scheme-2 by GC with saturated carisoprodol intermediates. As per the GC

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analysis the relevant olefin impurities were not detected in the carisoprodol API intermediates.
However, since the 0.67RRT impurity in Carisoprodol appears in the USP HPLC analysis
method, the same method was followed to analyse the penultimate compound 4 (N-Substituted
monocarbamate) in the USP HPLC method. To our surprise the prepared olefin
monocarbamate 8 from schem-2 has matched with RRT 0.60 in HPLC condition USP method
of compound 4.
Chromatographic studies (HPLC) with the 1% concentration and coinjection of
impurity 8 with compound 4 were also conducted and concluded that the same impurity was
carry over to next stage forming carisoprodol olefin impurity (0.67 RRT).
Experimental section
All materials were purchased from commercial suppliers. Unless specified otherwise,
all reagents and solvents were used as supplied by manufacturers. 1H NMR spectra and 13C
NMR spectra were recorded on a Varian 400 MR spectrometer in CDCl3 and DMSO-d6, and
mass spectra were determined on an API-2000LCMS mass spectrometer, Applied Biosystems.
High Performance Liquid Chromatography (HPLC).
An USP HPLC (Reference) method was performed for the analysis of Carisoprodol
and its potential impurities (Shimadzu series 1100 with empower software, binary pump,
variable wavelength detector, Waldbronn, Germany), where a column Inertsil C8-3 (4.6-mm
´ 15-cm; 4-mm) with a mobile phase consisting of A:Acetonitrile and water(1:3, v/v), B:
acetonitrile , with a timed gradient program of T/%B: 0/100, 0/100, 20/80, 20/80, 0/100, 0/100,
with a flow rate of 1.5 mL/min and UV detection at 200 nm was used. This HPLC method was
able to detect all the impurities.
Mass Spectrometry. The mass spectra were recorded on Schimadzu LCMS-QP8000 and
Micromass LCT Premier XE mass spectrometers.
NMR Spectroscopy. The 1H NMR spectra were recorded on a Bruker 300 MHz FT-NMR
spectrometer using CDCl3 as a solvent; the chemical shifts are reported in δ (ppm) relative to
TMS as internal standard. 13C and DEPT spectra were recorded on Bruker 300 MHz FTNMR
using CDCl3 as a solvent; the chemical shifts are reported in δ (ppm) relative to CDCl3 as
internal standard.
Experimental section
Preparation of 2-Propylidene-malonic acid diethyl ester 8.
To a solution of diethyl malonate (80.0 g, 0.499 mol, and 1.0 eq) in acetic anhydride
(80.0 g, 0.783 mol, and 1.57 eq) propionaldehyde (57.82 g, 0.994mol, and 2.0 eq) was charged
in an autoclave reactor. It was stirred for 12 hours at 120°C. The reaction mass was diluted
with DCM (400 mL) and washed with water (200 mL) followed by saturated sodium
bicarbonate solution (400 mL). The DCM layer was separated and concentrated. The crude
reaction mass was purified by high vaccum distillation at 120°C and 500mmHg pressure to
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afford 30 g of yellow oily liquid. 1HNMR (CDCl3, 300 MHz, δ ppm): 6.98 (t, 1H), 4.23 (m,
4H), 2.31 (m, 2H), 1.3 (t, 6H), 1.11 (t, 3H).

Preparation of 2-Methyl-2-propenyl-malonic acid diethyl ester 9.

To a stirred solution of diisopropylamine (18.18 g, 0.16 mol, 1.2 eq) in THF (150 mL)
and the resulting reaction mixture cooled to -15 °C, n-BuLi 1.6 M (114 mL, 0.18 mol, 1.21
eq) was added dropwise at -15°C under nitrogen atmosphere and the reaction mixture stirred
for 1 h. Hexamethyl phosphoramide (78 mL, 0.44 mol, 3.0 eq) was added dropwise to the
reaction mass at -15°C and stirred the reaction mixture for 15 minutes. The reaction mass was
cooled to -80°C and 2-propylidene-malonic acid diethyl ester ( 30.0 g, 0.14 mol, 1.0 eq) was
added dropwise and maintain the stirring for 15 minutes. Methyl iodide (35.08 g, 0.24 mol,
1.65 eq) in THF(40 ml) was added drop wise to the reaction mass at -80 °C , and the resulting
reaction mixture allowed to raise the temperature to 25°C , maintained stirring at 25°C for 1 h
and the resulting mixture heated to 65°C for 1 h. The reaction mass was quenched by DM
water (150 mL) followed by acidified with dilute HCl (200 mL). The reaction mass was
extracted with diethyl ether (450 mL) thrice and combined organic layer was dried on sodium
sulphate (10 g). The crude product thus obtained was purified through column chromatography
using ethyl acetate and hexanes (1:4 v/v) to afford pure product. 1HNMR (CDCl3, 300 MHz,
δ ppm): 5.94 (d, 1H), 5.6 (m, 1H), 4.18 (q, 4H), 1.7 (d, 3H), 1.5 (s, 3H), 1.25 (t, 6H).
Preparation of 2-Methyl-2-propenyl-propane-1, 3-diol 10.
To a stirred solution of 2-Methyl-2-propenyl-malonic acid diethyl ester (28 g, 0.130
mol, 1.0 eq) in toluene (280 mL) and the reaction mixture cooled to – 20 °C. DIBAL 1.0 M
solution in toluene (500 mL, 0.732 mol, and 5.6 eq) was added at -15 °C to -20 °C, the resulting
reaction mixture was stirred for 2 h. The reaction mixture was quenched by methanol (600
mL) and allowed to raise to 25°C and maintained for 0.5 h, filtered the solid and evaporated
the filtrate to afford diol as yellow oily liquid. 1HNMR (CDCl3, 300 MHz, δ ppm): 5.58 (m,
1H), 5.42 (d, 1H), 3.55 (q, 4H), 2.37 (bs, 2H), 1.7 (d, 3H), 1.0 (s, 3H).

Preparation of 5-Methyl-5-propenyl-[1, 3] dioxane 11.

To a stirred solution of 2-Methyl-2-propenyl-propane-1, 3-diol (5 g, 0.03 mol, 1.0 eq)
10 in dichloromethane (50 mL) was added pyridine (12.39 mL, 0.153 mol and 4.0 eq), and the
resulting reaction mixture cooled to – 70 °C. Triphosgene (11.39 g, 0.03 mol and 1.0 eq) was
added at – 70 °C, the reaction mixture was stirred for 0.5 h. Raised the temperature to 25 °C,
followed by quenched with saturated sodium bicarbonate solution (30 mL). The layers were
separated, followed by concentrated to afford crude compound. The crude product thus
obtained was purified through column chromatography using ethyl acetate and hexanes (2:4
v/v) to afford pure product as brown oily liquid. 1HNMR (CDCl3, 300 MHz, δ ppm): 5.73 (m,
1H), 5.35 (d, 1H), 4.25 (d, 4H), 1.7 (d, 3H), 1.0 (s, 3H). 13CNMR (CDCl3, 75 MHz, δ ppm):
δ18.4, δ20.8, δ23.8, δ67.0, δ68.23, δ125.9, δ133.0, δ171.6.
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 K. Arun Kumar, et al., J. Chem. & Cheml. Sci. Vol.7(4), 352-360 (2017)

Preparation of Isopropyl-carbamic acid 2-hydroxymethyl-2-methyl-pent-3-enyl ester 12

5-Methyl-5-propenyl-[1, 3] dioxane (2.5 g, 0.016 mol and 1.0 eq) 11and isopropyl
amine (9.46 mL, 0.16 mol and 10 eq) was charged into a clean autoclave reactor at 25°C and
allowed to stirr at 90°C for 3 h. The excess isopropyl amine was evaporated under reduced
pressure to afford crude. The crude product thus obtained was purified through column
chromatography using ethyl acetate and hexanes (1:4 v/v) to afford pure product as light
yellow coloured oily liquid, 1HNMR (CDCl3, 300 MHz, δ ppm): 5.6 (m, 1H), 5.4 (d, 1H), 4.6
(br, 1H), 3.95 (s, 2H), 3.8 (m, 1H), 3.3 (d 2H), 1.7 (d, 3H), 1.2 (d, 6H) 1.0 (s, 3H). 13CNMR
(CDCl3, 75 MHz, δ ppm): δ18.4, δ19.11, δ22.93, δ 42.3, δ 43.2 δ66.6, δ68.14, δ125.46, δ133.4,
δ156.63.
Preparation of Carbamic acid 2-isopropylcarbamoyloxymethyl-2-methyl-pent-3-enyl
ester 13.
To a stirred solution of Isopropyl-carbamic acid 2-hydroxymethyl-2-methyl-pent-3-
enyl ester (1.0 g, 0.0046 mol and 1.0 eq) 12 in toluene( 10 mL) and the resulting mixture was
cooled to – 10 °C. Sodium cyanate (0.33 g, 0.005 mol and 1.1 eq) was added at -10 °C,
followed by purged the dry HCl gas for 0.5 h and raised the temperature of the resulting
reaction mixture to 25 °C. Quenched the reaction mass by saturated bicarbonate solution (10
mL). The layers were separated, followed by concentrated to afford crude compound. The
crude product thus obtained was purified through column chromatography using ethyl acetate
and hexanes (2:4 v/v) as an eluent to afford the desired carisoprodol olefin impurity. . 1HNMR
(CDCl3, 300 MHz, δ ppm): 5.5 (m, 1H), 5.35 (d, 1H), 4.7 (br, 2H), 4.45 (br 1H) 3.9 (s, 4H),
3.7 (m, 1H), 1.6 (d, 3H), 1.1 (d, 6H) 0.95 (s, 3H). 13CNMR (CDCl3, 75 MHz, δ ppm): δ17.3,
δ18.4, δ21.9, δ28.67, δ 39.1, δ 43.2 δ67.1, δ67.7, δ124.4, δ131.7, δ154.6, δ155.9.

CONCLUSION

An efficient synthesis and characterization of the potential impurity of carisoprodol

drug has been described; in addition spiking studies were performed with USP method. This
study will provide an access to reference standard of this impurity and also helpful to
pharmaceutical industry for similar drugs.

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